02-20-2014, 03:05 AM
MEMBRANE POTENTIAL(Vm)
-most of the information here about membrane potential mainly refers to neurons
- The membrane potential is the electrical potential difference between the inside and outside of the cell across the cell membrane. It can be negative, zero or positive.
-let say the membrane is permeable only to one ion while impermeable to other ions and let say the concentration of that ion is higher on one side. Then as the ion diffuses due to its concentration gradient, it will generate a potential difference generated across the cell membrane called DIFFUSION POTENTIAL defined as the potential difference generated across the cell membrane because of concentration gradient of an ion. as the ion diffuses due to its concentration gradient, it will reach a diffusion potential at which the force due to concentration gradient is equal to the force due to electrical gradient so there is no net diffusion of the ion across the membrane. This diffusion potential is called the electrochemical EQUILIBRIUM POTENTIAL for that ion and it can be calculated by the NERNST EQUATION for that ion( E ion or ENa for ex) at a given concentration gradient of the ion
-If the membrane is permeable to more ions for ex to Na, K, Cl but not to negative charged proteins, the membrane potential can be calculated by using the GOLDMAN-hodgkin-Katz EQUATION, that takes in consideration electrochemical gradient and permeability of each ion
-ions can move through the cell membrane by: a) active transport via a pump for ex Na- K ATPase b) diffusion via ion channels of 3 types: 1) ungated or leaky channels so they are always open for ex K leaky channels or I funny sodium channels in SA node 2) ligand- gated channels, closed until they bind to the ligand 3) voltage gated channels, they are closed at RMP but open when the membrane potential reaches certain value. There are also mechanically-gated ion channels. In graded and action potential, the movement of ions through the cell membrane is by passive diffusion, not by active transport.
-Let see the different values of the membrane potential during 1) resting membrane potential 2) graded potential and 3) action potential
I) RESTING MEMBRANE POTENTIAL(RMP)
- in most neurons the typical measured resting membrane potential of −70 mV(values vary form different authors)
- What is the resting membrane potential for Nerves? Heart Pacemaker? Skeletal Muscle?
Nerves = -90mv Heart Pacemaker = -60mv Skeletal Muscle = -83 mv
-the value of the resting membrane potential (RMP) depends on 1) RMP mainly due to High K conductance and some Na conductance 2) Na- K pump 3) the donnan effect
- the RMP is mainly due to High K conductance and some Na conductance. The Nernst equation for chlorine is close to the RMP so it does not contribute to it. So the RMP can be calculated using the goldman equation that includes Na, K
-at rest the membrane is more permeable to K(via leaky channels) than Na so more K diffuses out so the RMP is negative and close to the Nernst equation of K. But the RMP is not equal to the Nernst equation of K because Na diffuses in, making it less negative than the Nernst equation of K.
-in the RMP, more than one ion contribute to the membrane potential across the plasma membrane (Vm) of a cell so RMP=Vm is calculated by GOLDMAN-hodgkin-Katz EQUATION
- When two or more ions contribute to the membrane potential across the plasma membrane (Vm) of a cell, it is likely that the membrane potential would not be at the equilibrium potential (E ion.) for any of the contributing ions. So no ion would be at its equilibrium (i.e., E ion not = Vm of RMP). For example, the resting membrane potential of a typical neuron is neither at the K+, Na+, nor Cl− equilibrium potential).For example the ENa not = Vm of RMP. This means that at the resting potential, Na+ is not at its electrochemical equilibrium and, thus, the chemical and electrical forces acting on Na are not equal.
- if the membrane potential is not exactly at the equilibrium potential for an ion, then an ELECTROCHEMICAL DRIVING FORCE(VDF) acts on the ion, causing the net movement of the ion across the membrane down its own electrochemical gradient( causes the ion to flow into or out of the cell). The driving force is quantified by the difference between the membrane potential and the ion equilibrium potential (VDF = Vm of RMP – E ion.). The driving force is the net ELECTROMOTIVE FORCE (EMF) that acts on the ion. The magnitude of the driving force indicates how far the membrane potential (Vm of RMP) is from the electrochemical equilibrium (E ion.) of an ion. Thus, the magnitude of the driving force indicates how far an ion is from its equilibrium. The arithmetic sign (i.e., positive or negative) of the driving force acting on an ion along with the knowledge of the valence of the ion (i.e., cation or anion) can be used to predict the direction of ion flow across the plasma membrane (i.e., into or out of the cell). Vm of RMP is calculated by using the Goldman-Hodgkin-Katz equation. E ion is calculated for each ion by using the Nernst equation.
-in the RMP, the rate at which an ion moves across a membrane depends on its NET FORCE or ELECTROCHEMICAL DRIVING FORCE(net EMF= VDF) and its conductance across the membrane. For ex Na has high EMF but low permeability.
-For chlorine, the measured Vm of RMP= is equal to the calculated E Cl- so chlorine is at its equilibrium, VDF=0 = Vm of RMP – E Cl. And so no matter what the membrane conductance to chlorine is, there will not be a net diffusion of chloride ions and a change in Cl membrane conductance will not result in net diffusion of chloride ions because VDF=0
-For potassium, the measured Vm of RMP= is NOT equal to the calculated E K- so K is NOT at its equilibrium, VDF== Vm of RMP – E K, VDF not=0, VDF is about 5mv, it is a small force so K is close to its electrochemical equilibrium. There are leaky or ungated K channel open at all times so there is net diffusion of K ions to the ouside of the membrane. Increasing K CONDUCTANCE will accelerate the efflux of K ions and hyperpolarize the cell. The K driving force can be changed by altering extracellular K concentration. INCREASING ECF K CONCENTRATION will decrease the net driving force of K (VDF== Vm of RMP – E K) -- > reduce the efflux of K ions or even create an efflux of K ions resulting in DEPOLARIZATION. On the other hand, DECREASING ECF K CONCENTRATION will increase the net driving force of K (VDF== Vm of RMP – E K) -- > increase the efflux of K ions resulting in HYPERPOLARIZATION. So the cell’s RMP is very sensitive to changes in the ECF K ion CONCENTRATION because the membrane PERMEABILITY of K at RMP is so much higher than of Na. that’s why hypokalemia or hyperkalemia result in cardiac electrical effects (and the pt dies before you see CNS electrical effects) while hyponatremia or hypernatremia does not affect the heart electrical activity but it affects the CNS due to CNS edema or shrinking resulting in seizures
If we have a higher than normal K permeability, what will happen to the membrane potential?
It will get closer to the Nerst potential of K, this will make the cell more negative, bc K is leaving the cell. Hyperpolarization.
At RMP an outward current is generated by a small amount of potassium ions leaking out of the cell through potassium-selective leak channels. This slow leak of positively charged potassium ions means that the internal cell membrane becomes slightly negatively charged compared to the outside; this gives rise to the negative resting membrane potential, which for neurons is around -70 mV.
-For sodium, the measured Vm of RMP= is NOT equal to the calculated E Na- so Na is NOT at its equilibrium, VDF== Vm of RMP – E Na, VDF not=0, VDF is about 135mv, it is a large force so Na is very far away from its electrochemical equilibrium. In resting conditions there is not a significant number of open Na channels so at RMP the Na CONDUCTANCE is close to zero. So at RMP even though the Na driving force is high, the influx of Na is very low due to the very low Na conductance at RMP. Increasing Na CONDUCTANCE will increase the influx of Na ions, resulting in DEPOLARIZATION. Because Na channels are closed under resting conditions, change in ECF Na CONCENTRATION will not affect the resting membrane potential. So the cell’s RMP is NOT sensitive to changes in the ECF Na ion CONCENTRATION because the membrane PERMEABILITY of Na at RMP is very low. that’s why hyponatremia or hypernatremia does not affect the heart electrical activity but it affects the CNS due to CNS edema or shrinking resulting in seizures
Does threshold generation depend on calcium?
When EC concentration of Ca is lowered what happens to the probability that a Na channel will be opened at any voltage?
It is increased
A smaller than normal amount of depolarization will bring an excitable membrane to its firing threshold.
Hypocalcemia causes an increase in neuromuscular irritability...hypocalcemic tetany, laryngospasms can cause respiratory failure.
If EC concentration of Ca is raised, what happens to the probability that a Na channel will be opened at a certain voltage?
It will be decreased.
Can shift excitable membrane threshold so that a larger amount of depolarization is needed to bring membrane to the firing level.
Causes decrease in neuromuscular irritability-fatigue, lethargy, muscle weakness and diminished reflexes, mental confusion.
1a Maintenance of the Resting Membrane Potential in STEADY STATE
-GENESIS of the RMP is mainly due to High K conductance and some Na conductance. MAINTENANCE of the RMP is mainly due to Na- K pump
-the value of the resting membrane potential (RMP)depends are 1) RMP mainly due to High K conductance and some Na conductance 2) Na- K pump(5-10% of RMP) 3) the donnan effect(small % of RMP)
__________ Na- K pump________
- Na- K pump has two functions: 1) In small amount the Na- K pump directly contributes to the RMP( 5-10% of the RMP, direct ELECTROGENIC contribution of the pump) by pumping out a net 1 positive charge(3Na out-2K in=1Na out) making the membrane more negative inside 2) maintenance of the Na and K concentration gradients so the Na-K contributes indirectly to the RMP.
-The Na-K pump maintains constant the Na and K concentration gradients in a STEADY STATE. In steady state free energy is required to maintain the constant resting membrane potential and ionic gradient. In DONNAN EQULIBRIUM no free energy is required
- Since in most cells Vm of RMP is not at the equilibrium potential for either K+, or Na+, at the resting membrane potential, each ion is moving down its own electrochemical gradient according to the driving force acting on the ion. Thus, it is clear that under resting physiological conditions, there is constant efflux of K+ from the cell, influx of Na+ into the cell. Therefore, if the ionic concentration gradients are not maintained, in the long run, because of the constant ionic fluxes across the plasma membrane, the concentration gradients will be DISSIPATED. Cells avoid this situation by having a primary active transporter (i.e., pump) which pumps Na+ out of the cell and K+ into the cell to counteract the constant movements of these two ions down their electrochemical gradients. This protein is the Na+/K+ ATPase which couples the hydrolysis of one ATP molecule to moving 3 Na+ ions out of the cell and 2 K+ ions into the cell.
--To maintain the concentration gradients for Na+ and K+, it is necessary to transport Na+ out of the cell and K+ back into the cell. The Na+/K+-ATPase performs this function. This pump is essential for the maintenance of Na+ and K+ concentrations across the membrane. If this pump stops working (as occurs under anoxic conditions when ATP is lost), or if the activity of the pump is inhibited (as occurs with cardiac glycosides such as digitalis, ouabain), Na+ accumulates within the cell and intracellular K+ falls. This causes DEPOLARIZATION of the resting membrane potential. Furthermore, it is important to note that this pump is electrogenic in nature because it extrudes 3 Na+ for every 2 K+ entering the cell. By pumping more positive changes out of the cell than into the cell, the pump activity creates a negative potential within the cell. This potential may be up to -10 mV. Inhibition of this pump, therefore, causes depolarization resulting not only from changes in Na+ and K+ concentration gradients, but also from the loss of an electrogenic component of the membrane potential.
-If the activity of the Na+/K+ ATPase is inhibited in a cell (for example with ouabain) initially the membrane potential is not altered (or is altered very slightly). However, if the pump is not allowed to function for a long period of time (> tens of seconds), the membrane potential begins to become less negative until it ultimately completely disappears (i.e., Vm = 0 i.e. it will be halfway between the Na and K Nernst equilibrium potentials, which is approximately 0). This is because constant Na+ influx into the cell and K+ efflux out of the cell serve to decrease the transmembrane Na+ and K+ concentration gradients leading to a membrane potential of close to zero or the average of the Nernst potential of K and Na. Thus, in order to maintain the membrane potential, cells have to expend energy to maintain the proper intracellular Na+ and K+ concentrations. Therefore, although the Na+/K+ ATPase is not responsible for the generation of the membrane potential, it is responsible for its maintenance by maintaining the normal intracellular K+ and Na+ concentrations.
At this point, it may be wondered what maintains the extracellular concentrations of K+ and Na+. The kidneys are responsible for maintaining the low extracellular K+ concentration and the high extracellular Na+ concentration. The kidneys (urinary system) working in conjunction with the endocrine system are responsible for extracellular K+ and Na+ homeostasis.
--after an action potential, the membrane potential is brought back from hyperpolarization to RMP by Na-K ATPase
---after an EPSP graded potential, the membrane potential is brought back from the subthreshold depolarization to RMP by Na-K ATPase
---after an IPSP graded potential, the membrane potential is brought back from the hyperpolarization to RMP by Na-K ATPase
What would happen if all the Na/K ATPases were poisoned with Ouabain in an axon? Would the action potential immediately stop?
Blocking the sodium potassium pump leads to a gradual influx of sodium into the cell, and efflux of potassium out of the cell. These changes in concentration lead to a change in the equilibrium potential for potassium, as well as for sodium. As the equilibrium potential for potassium becomes more positive, the resting membrane potential becomes more positive (i.e., more DEPOLARIZED). Because of the sodium influx into the cell, the equilibrium potential for sodium is changed, namely, it is less positive. And because the peak amplitude of the action potential is dependent upon the value of the sodium equilibrium potential, the peak amplitude of the action potential would also decrease over time.
Initially the Nerve cell can fire thousands of action potentials even if Na/K pump is poisoned bc only relatively few ions are needed to move in or out of the cell to change membrane potential. Ion gradients would slowly disappear though resulting in decrease frequency and amplitude of action potentials. Once ion gradients are disturbed enough, there are no more action potentials.
__________ouabain and digoxin (Cardiac glycosides) __________
Drugs such as ouabain and digoxin are cardiac glycosides. Digoxin from the foxglove plant is used clinically, whereas ouabain is used only experimentally due to its extremely high potency.
Normally, sodium-potassium pumps in the membrane of cells (in this case, cardiac myocytes) pump potassium ions in and sodium ions out. Cardiac glycosides inhibit this pump by stabilizing it in the E2-P transition state, so that sodium cannot be extruded: intracellular sodium concentration therefore increases. A second membrane ion exchanger, NCX, is responsible for 'pumping' calcium ions out of the cell and sodium ions in (3Na/Ca); raised intracellular sodium levels inhibit this pump, so calcium ions are not extruded and will also begin to build up inside the cell.
Increased cytoplasmic calcium concentrations cause increased calcium uptake into the sarcoplasmic reticulum via the SERCA2 transporter. Raised calcium stores in the SR allow for greater calcium release on stimulation, so the myocyte can achieve faster and more powerful contraction by cross-bridge cycling. The refractory period of the AV node is increased, so cardiac glycosides also function to regulate heart rate.
Binding of cardiac glycoside to Na-K ATPase is slow, and also, after binding, intracellular calcium increases gradually. Thus, the action of digitalis (even on IV injection) is delayed.
Raised extracellular potassium decreases binding of cardiac glycoside to Na-K ATPase. As a consequence, increased toxicity of these drugs is observed in the presence of Hypokalemia.
If SR calcium stores become too high, some ions are released spontaneously through SR ryanodine receptors. This effect leads initially to bigeminy: regular ectopic beats following each ventricular contraction. If higher glycoside doses are given, rhythm is lost and ventricular tachycardia ensues, followed by fibrillation.
__________Donnan Effect__________
- the donnan effect also contributes to the RMP by maintaining the diffusion gradient for K. The RMP is at steady state but not at donnan equilibrium.
When an ion on one side of a membrane cannot diffuse through the membrane, the distribution of other ions to which the membrane is permeable is affected in a predictable way. For example, the negative charge of a nondiffusible anion hinders diffusion of the diffusible cations and favors diffusion of the diffusible anions. Donnan and Gibbs showed that in the presence of a nondiffusible ion, the diffusible ions distribute themselves so that at equilibrium their concentration ratios are equal: the Gibbs–Donnan equation. It holds for any pair of cations and anions of the same valence.
The Donnan effect on the distribution of ions : because of charged proteins (Prot–) in cells, there are more osmotically active particles in cells than in interstitial fluid, and because cells have flexible walls, osmosis would make them swell and eventually rupture if it were not for Na, K ATPase pumping ions back out of cells. Thus, normal cell volume and pressure depend on Na, K ATPase.
II) GRADED POTENTIAL
A graded potential is local(travels in small regions of the plasma membrane), a graded(refers to the magnitude of the potential change) response to a stimulus. They are subthreshold. These graded potentials "add" together (exhibit spatial and temporal summation ) and if the membrane potential if it becomes large enough to reach the threshold it produces an action potential.
http://i.imgur.com/gVO3WG9.png
in this image, a,b,c are subthreshold graded potential and do NOT trigger action potential, while d is a graded potential that reaches threshold and triggers action potential
Graded potential is a depolarization or hyperpolarization of a neuron that varies in amplitude.
An action potential is not graded and is all or nothing.
-Graded potentials generates local current. Graded potential propagate by local current or electrotonic conduction. In neurons the graded potentials are generated in the dendrites or soma and then travel by local current or electrotonic conduction to the first node of ranvier , located close to the AXON HILLOCK, where the action potential will be generated, i.e. the graded potential will bring the membrane potential in the axon hillock to threshold and here VOLTAGE GATED sodium channels will open to generate the action potential. The initial segment of the axon(near axon hillock) is rich in VOLTAGE GATED sodium channels. Dendrites have few voltage-gated sodium channels. As such the capability of these structures in generating action potentials is extremely limited. Therefore, the transmission of the electrical signal in the dendrite is via a non action potential mechanism, electrotonic conduction.
So from dendrites and soma up to the initial segment of the axon the impulse travels by graded potential. From the axon hillock to the axon terminal and synapse the impulse travels by action potential
-Graded potentials are conducted with decrement. i.e. the amplitude or magnitude falls off the further you get from the point of origin. Decrement think DECREASE. They decrease in magnitude the further they get from the origin. Why does decrement occur in graded potentials? Because charges are lost across the membrane because of “leaky” channels as the graded potential is conducted and the magnitude of the membrane potential decreases with distance from the site of origin(charge density falls)
How far can a graded potential travel? 1-2mm of the origin. Graded potentials die out in 1-2mm of the origin
-Graded potential and the local current they generate can function as signals over very short distances and some cells use to transmit signals only by generating graded potentials without generating action potential for ex bipolar cells of the retina generate graded potential but not action potential.
- Graded potentials serve as the only communication in some neurons.
__________Algebraic summation of graded potentials__________
Graded potentials are subject to summation, spatially and/or temporally.
Spatial summation: If a cell is receiving SIMULTANEOUSLY 2 or more inputs at synapses that are near each other, their postsynaptic potentials add together. If the cell is receiving two excitatory postsynaptic potentials, they combine so that the membrane potential is depolarized by the sum of the two changes. If there are two inhibitory potentials, they also sum, and the membrane is hyperpolarized by that amount. If the cell is receiving both inhibitory and excitatory postsynaptic potentials, they can cancel out, or one can be stronger than the other, and the membrane potential will change by the difference between them.
Temporal summation: When a cell receives inputs that are close together in time(separated in TIME), they are also added together, even if from the same synapse. Thus, if a neuron receives an excitatory postsynaptic potential, and then the presynaptic neuron fires again, creating another EPSP, then the membrane of the postsynaptic cell is depolarized by the total of the EPSPs.
_______________Conduction of graded potential_______________
-graded potential is conducted from one point of the membrane to the next point by ELECTROTONIC CONDUCTION or LOCAL CURRENTS, i.e. without crossing the membrane the ions move from high potential difference to low potential difference(from depolarized area to undepolarized area inside the membrane and viceversa in the outside of the membrane). A local current flow shows SPACE (LENGTH) CONSTANT and TIME CONSTANT
http://i.imgur.com/obCqaMG.png
the image shows mechanism of electrotonic spread of depolarization. A, The reversal of membrane polarity that occurs with local depolarization. B, The local currents that flow to depolarize adjacent areas of the membrane and allow conduction of the depolarization
What is the space constant or Length constant?
A way to prove that through distance, the voltage gets smaller. After one space constant it is 37% of the maximum voltage(membrane potential)(it is decayed by 63% from its peak value ) .
Is the distance between the injection site of a current at one point of an axon and the point where the steady state transmembrane voltage change has decayed by 63% from its peak value.
Local potentials (graded potentials)would decrease to almost nothing after several length constants. Local potential traveling down an axon dies away bc some current is leaking out across the membrane resistance (Rm).
- The magnitude of the potential change decreases exponentially with distance from the site of origin. The distance over which the potential change decreases to 1/e (37%) of its maximal value is called the length constant or space constant (e is the base of natural logarithms and is equal to 2.7182). A length constant of 1 to 3 mm is typical for mammalian axons
-Length constant is defined as the distance in which a change in membrane potential declines to 37% of the initial value. Thicker processes like dendrites have higher length constants which helps in passive conduction and contributes to spatial summation. Axons are thinner and have smaller length constants, this is why they need active conduction (via APs) to provide repetitive amplification of the potential change along its length.
What is the time constant?
The amount of time it takes for a voltage to change by a certain percentage (63%) of the eventual new stead state value. This shows that signals go away fast.
Current from a cell membrane does not immediately change membrane potential bc the cell membrane acts as a capacitor.
This is like RC circuits. The time constant is a function of an axon's electrical resistance and capacitance.
t=RC
Takes time to charge and discharge.
http://o.quizlet.com/i/wbI8jj5AOAh0eqoiG4_xgA.jpg
Time constant: (tau) time it takes to charge the membrane to 63% of the final membrane potential. It is a function of membrane resistance X membrane capacitance. Basically, the higher the time constant, the slower the membrane changes voltage. Dendrites and soma have high time constants which contributes to temporal summation of synaptic activity
MS decrease in Space constant
MS INcrease in Time constant
What is membrane capacitance?
the ability of a membrane to maintain separate charges
__________Types of graded potentials__________
There are 4 types of graded potentials. They are the end plate potential(EPP and MEPP), pacemaker potential, generator potentials or receptor potentials and post synaptic membrane potential(PSP like IPSP or EPSP).
__________a) Generator (Receptor) potential__________
-sensory receptors (ex mechanoreceptors, thermoreceptors, nociceptors, chemoreceptors[ex taste buds] and electromagnetic receptors[vision]) respond to stimuli by generating graded potential called generator potential or receptor potential
-Receptor potential, a type of graded potential, is the transmembrane potential difference of a sensory receptor
-A receptor potential is often produced by sensory transduction. It is generally a depolarizing event resulting from inward current flow(exception, light in photoreceptors causes hyperpolarization). The influx of current will often bring the membrane potential of the sensory receptor towards the threshold for triggering an action potential.
-if the graded potential reaches a threshold and an action potential is generated and the sensory information is sent to the spinal cord and brain
-for example a light touch is detected by Meissner corpuscles, receptors in the skin. Many of these are found next to hair follicles so even if the skin is not touched directly, movement of the hair is detected. The light movement of a hair opens mechanically-gated sodium channels producing a generator potential. Deforming the corpuscle creates a generator potential in the sensory neuron arising within it. This is a graded response: the greater the deformation, the greater the generator potential. If the generator potential reaches threshold, voltage-gated sodium channels are opened that triggers an action potential at the first node of Ranvier of the sensory neuron. Once threshold is reached, the magnitude of the stimulus is encoded in the frequency of impulses generated in the neuron. So the more massive or rapid the deformation of a single corpuscle, the higher the frequency of nerve impulses generated in its neuron.
-So the mechanically-gated sodium channels producing a generator potential while the voltage-gated sodium channels generate an action potential
__________b) Pacemaker potential__________
-The SA node has Leaky Na I funny Channels that generate graded potential causing slow depolarization of the cell toward the threshold(phase 4) and then opening of voltage-gated Ca2+ channels generate the action potential(phase 0)
-graded potential is responsible for cardiac automaticity
__________c) Postsynaptic potential__________
-Postsynaptic membrane potentials are graded potentials generated in the postsynaptic membrane during synaptic transmission. Postsynaptic potentials are changes in the membrane potential of the postsynaptic terminal of a chemical synapse.
-They are caused by the presynaptic neuron releasing neurotransmitters from the terminal bouton at the end of an axon into the synaptic cleft. The neurotransmitters bind to receptors on the postsynaptic neuron and many of these receptors contain an ion channel [ligand-gated ion channel or ionotropic receptors] that opens upon binding of the neurtransmitter and allow of passing positively or negatively charged ions either into or out of the cell.
--Postsynaptic potentials can be excitatory postsynaptic potential (EPSP) orinhibitory postsynaptic potential (IPSP),
Excitatory Postsynaptic Potential (EPSP)
Usually Na or Ca moving down their concentration gradients causing depolarization
Inhibitory Postsynaptic Potential (IPSP)
movement of Cl and K down their concentration gradients causing hyperpolarization
____________________Excitatory postsynaptic potential_____________
-If the opening of the ion channel results in a net gain of positive charge across the membrane, the membrane is said to be depolarized, as the potential comes closer to zero. This is an excitatory postsynaptic potential (EPSP), as it brings the neuron's potential closer to its firing threshold (about -50mV). For example acetylcholine
-an excitatory postsynaptic potential (EPSP) is a temporary depolarization of postsynaptic membrane potential caused by the flow of positively charged ions into the postsynaptic cell as a result of opening of ligand-gated ion channels. EPSPs can also result from a decrease in outgoing positive charges.
-EPSPs, like IPSPs, are graded (i.e. they have an additive effect). When multiple EPSPs occur on a single patch of postsynaptic membrane, their combined effect is the sum of the individual EPSPs. Larger EPSPs result in greater membrane depolarization and that brings the membrane potential upto the threshold and opening of voltage gated sodium channels to start firing an action potential.
-When an active presynaptic cell releases neurotransmitters into the synapse, some of them bind to receptors on the postsynaptic cell. These receptors contain an ion channel capable of passing positively charged ions into the cell (at excitatory synapses, the ion channel typically allows SODIUM into the cell, generating an excitatory postsynaptic current). This depolarizing current causes an increase in membrane potential, the EPSP.
-The neurotransmitter most often associated with EPSPs is the amino acid glutamate, and is the main excitatory neurotransmitter in the central nervous system.
____________________ Inhibitory postsynaptic potential______________
-If the opening of the ion channel results in a net gain of negative charge, this moves the potential further from zero and is referred to as hyperpolarization. This is an inhibitory postsynaptic potential (IPSP), as it changes the charge across the membrane to be further from the firing threshold. inhibitory postsynaptic potentials (IPSPs) usually result from the flow of negative ions into the cell or positive ions out of the cell.
Some common neurotransmitters involved in IPSPs are GABA and glycine that bind their receptors and result in increased entry of chloride into cells . GABA binds to GABAA receptors that are ion channels. GABA is the most common neurotransmitter associated with IPSPs in the brain.
This system[1] IPSPs can be temporally summed with subthreshold or suprathreshold EPSPs to reduce the amplitude of the resultant postsynaptic potential. Equivalent EPSPs (positive) and IPSPs (negative) can cancel each other out when summed. The balance between EPSPs and IPSPs is very important in the integration of electrical information produced by inhibitory and excitatory synapses.
Neurotransmitters are not inherently excitatory or inhibitory: different receptors for the same neurotransmitter may open different types of ion channels.
__________d) End-plate potential__________
-In the neuromuscular junction of vertebrates, EPP (end-plate potentials) are mediated by the neurotransmitter acetylcholine, which is also the main transmitter in the central nervous system of invertebrates.[citation needed]
-End-plate potentials are graded potentials that develop at the postsynaptic end-plate membrane in the neuromuscular junction. They are always stimulatory(depolarization)
-End plate potentials (EPPs) are the depolarizations of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction. They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucer-like appearance.
-When an action potential reaches the axon terminal of a motor neuron, depolarization of the presynaptic terminal opens Ca channels, Calcium rushes causes the synaptic vesicles carrying acetylcholine to fuse with the PM and empty their contents into the cleft(NMJ) by exocytosis. Acetylcholine binds into nicotinic acetylcholine receptors which is also Na and K ion channel. Because the ligand-gated channel conducts both Na and K ions, the postsynaptic membrane is depolarized halfway between the Na and K nernest equilibrium potentials(approximately 0)
-A skeletal muscle action potential is generated when the motor endplate potential is sufficient to raise the surrounding sarcolemmal potential above the threshold for activation of the VOLTAGE GATED Na+ channels that are abundant throughout the sarcolemma. When these channels are activated, the membrane is rapidly depolarized towards the Nernst potential for Na+ (Table 1). However, the peak potential achieved is approximately +30 mV. The Nernst potential is not achieved for two main reasons. First, just as the Na+ channels are activated by membrane voltage changes, a process of inactivation is also initiated as the membrane potential becomes less negative. Inactivation is a slower mechanism than activation, so the Na+ current continues to flow for a short period after the onset of inactivation, but not sufficiently to reach the Nernst potential. The second factor limiting the upstroke of the action potential is the voltage activation of rectifying potassium channels. Their activation is initiated also during the upstroke of the action potential but (in a similar way to Na+ channel inactivation) there is a slight delay in channel opening. The resulting K+ current, in addition to limiting the peak of the action potential, is also principally responsible for repolarization.
Once an action potential has been generated, it spreads as a wave over the sarcolemma. Skeletal muscle sarcolemma is characterized by invaginations called transverse- or T-tubules that run perpendicular to the surface of the cell deep into its body. By passing down the t-tubular membrane, the action potential is carried to the structures responsible for transducing an electrical into a chemical signal that will trigger activation of the contractile elements. Depolarization of the T-tubules causes a conformational change in its dihydydropyridine receptor, which opens Ca release channels(RYNODINE receptors) in the nearby SR, causing the release of Ca from the sarcoplasmatic reticulum. Then the intracellular calcium binds to troponin C, etc
-the acetylcholine contained in ONE synaptic vesicle(quantum) produces a MINIATURE End plate potential (MEPP), the smallest possible EPP. MEPP is less than 1mV in amplitude and not enough to reach threshold. MEPPs summate to produce a suprathreshold EPP that can depolarize the membrane potential up to the threshold and open voltage gated Na channels to result in action potential of the muscle cell
_______________Clinical applications___________
-Lambert-Eaton myasthenic syndrome(LEMS) and botulism cause Dysfunction in quantal Ca-mediated synaptic vesicle release mechanism to produce EPP but no effect on MEPP (because a synaptic vesicle can be releases SPONTANEOUSLY, without Calcium mediated, and produce MEPP)
-LEMS decreases vesicles exocytosis resulting in: decrease EPP, NRL MEPP
-BOTULIN toxin causes total blockade of vesicles exocytosis resulting in: no EPP(EPP=MEPP), NRL MEPP. Botulinum toxin produced by the bacteria Clostridium botulinum is the most powerful toxic protein. It prevents release of acetylcholine at the neuromuscular junction by inhibiting DOCKING of the neurotransmitter vesicles.
- Myasthenia Gravis(MG)-- antibodies directed against the AChR- -> fewer AChRs are opened by each quantum of ACh release, and the amplitude of the MEPP is reduced. Fewer MEPPs are generated and the EPP is lower.
- Alpha-latrotoxin, a large protein toxin, found in black widow spiders causes pokes in the PM and destabilizes cell membranes by opening (acts as) Calcium channels resulting in a massive influx of calcium at the axon terminal causing massive exocytosis of acetylcholine and norepinephrine from nerve terminals, depleting its stores of acetylcholine from presynaptic nerve terminals.. This causes HYPOCALCEMIA and tetany. Clinically,Black widow spider causes painful muscle spasms with severe abdominal pain,, hypocalcaemia and tetany, followed by weakness. The treatment is Calcium gluconate and Black widow spider (Latrodectus mactans) antivenom called lexicomp
- curare acts post-synaptically, it compettitvely inhibits acetylchole from binding to its nicotinic ACh receptors in the NMJ. Curare is a classic antagonist of nicotinic AChRs and competes with acetylcholine for the binding site, which is effective as a neuromuscular blocking agent (nondepolarizing blocker) for general anesthesia.
Curare decreases the AMPLITUDE of both MEPPs and EPPs but NORMAL FREQUENCY of both MEPPs and EPPs
Curare is a competitive inhibitor of ACh, hence it will inhibit or reduce the amplitude of the miniature end-plate potential. Since curare affects the amplitude of the miniature end-plate potential, it would also affect the amplitude of the end-plate potential through the same mechanisms, competitive inhibition of ACh for its receptor.
Curare effects the ACh receptors on the postsynaptic side of the synapse. Hence, it will have no effect on the release of transmitter from the presynaptic terminal.
The frequency of MEPPs would not be affected. The frequency of MEPPs is determined strictly by the levels of basal calcium in the presynaptic terminal. Curare is a competitive antagonist of ACh, hence it would affect the amplitude of the miniature end-plate potential, but not the frequency.
__________________Graded Potentials versus Action Potentials_________________
GRADED potential: its amplitude is proportional to stimulus strength, exhibits summation, conduction is decremental with distance, not propagated
ACTION potential: its amplitude is independent of stimulus strength(all or none), does not exhibit summation, conduction is non-decremental with distance, propagated unchanged in magnitude
http://i.imgur.com/h9xf0j4.png
here in the image only the green color graded potential reaches threshold to initiate action potential
III) ACTION POTENTIAL(AP)
-Action potential is a property of excitable cells (i.e., nerve, muscle) that consists of a rapid depolarization, or upstroke, followed by repolarization of the membrane potential. Action potentials have stereotypical size and shape, are propagating, and are all-or-none.
http://i.imgur.com/xX73Lvs.png
figure shows APs in 3 different tissues
__________A) Phases of the action potential __________
Here is the SEQUENCE of an action potential in a nutshell
1. RMP due to leaky ungated K channels
2. GRADED potential is generated by ligand or mechanical gated ion channel
3. threshold voltage is reached
4. V.D. Na+ gates begin to open(opening of activation gate)-- > DEPOLARIZATION
5. V.D. K+ gates begin to open
6. Na+ gates begin to close
7. membrane REPOLARIZATION begins and continues up to HYPERPOLARIZATION
8. V.D. K+ gates close
9. Membrane potential is brought from hyperpolarization to RMP by Na-K ATPase
-__________the resting membrane potential(RMP )__________
is approximately −70 mV, cell negative.
is the result of the high resting conductance to K+, which drives the membrane potential toward the K+ equilibrium potential.
The high resting conductance to K+ is due to the ungated leaky K channels
At rest, the Na+ channels are closed and Na+ conductance is low.
-at RMP, all voltage gated Na and K channels are CLOSED
-__________from RMP to threshold__________
-a GRADED potential will bring the RMP to the threshold by opening LIGAND GATED or mechanically-gated ion channels.
- Threshold is the membrane potential at which the action potential is inevitable. At threshold potential, net inward current becomes larger than net outward current. The resulting depolarization becomes self-sustaining and gives rise to the upstroke of the action potential. If net inward current is less than net outward current, no action potential will occur (i.e., all-or-none response).
http://i.imgur.com/F0oocxD.png
__________DEPOLARIZATION(from threshold to upstroke)__________
2. Upstroke of the action potential
1. depolarization of the the membrane potential to threshold causes rapid opening of the activation gates of the voltage gated Na+ channel, and the Na+ conductance of the membrane promptly increases.
2. The Na+ conductance becomes higher than the K+ conductance, and the membrane potential is driven toward (but does not quite reach) the Na+ equilibrium potential of +65 mV. Thus, the rapid depolarization during the upstroke is caused by an inward Na+ current.
3. The overshoot is the brief portion at the peak of the action potential when the membrane potential is positive. However, the peak potential achieved is approximately +30 mV. The Nernst equilibrium potential of sodium is not achieved for two main reasons. First, just as the Na+ channels are activated by membrane voltage changes, a process of inactivation is also initiated as the membrane potential becomes less negative. Inactivation is a slower mechanism than activation, so the Na+ current continues to flow for a short period after the onset of inactivation, but not sufficiently to reach the Nernst potential. The second factor limiting the upstroke of the action potential is the voltage activation of rectifying POTASIUM channels. Their activation is initiated also during the upstroke of the action potential but (in a similar way to Na+ channel inactivation) there is a slight delay in channel opening. The resulting K+ current, in addition to limiting the peak of the action potential, is also principally responsible for repolarization.
4. Tetrodotoxin (TTX) and lidocaine block these voltage-sensitive Na+ channels and abolish action potentials.
- Tetrodotoxin is a poison found in the certain poisonous fishes such as pufferfish and triggerfish which blocks the VOLTAGE-GATED sodium ion channels, impacting both the initiation and the propagation of action potentials in the motor neuron.
Local anesthetics are hydrophobic molecules that bind to voltage-sensitive Na+ channels, inhibiting sodium transport and, consequently, also the action potential responsible for the nerve impulse.
Internal block of axonal voltage-gated sodium channels: Local anaesthetic drugs, such as lidocaine, cross the membrane lipid bilayer to enter the cell where they become polarised. The polar form of the drug is more readily able to block the voltage-gated sodium channel in its active state - this is called state dependent block.
Voltage-gated Na+ channels can exist in any of three distinct states: deactivated (closed), activated (open), or inactivated (closed).
-At the peak of the action potential, when enough Na+ has entered the neuron and the membrane's potential has become high enough, the Na+ channels inactivate themselves by closing their inactivation gates. once they are inactivated (closed), they will not respond to a second stimuli until the membrane potential repolarizes to the RMP
- When the membrane's voltage becomes low enough, the inactivation gate reopens and the activation gate closes in a process called deinactivation, or removal of inactivation. With the activation gate closed and the inactivation gate open, the Na+ channel is once again in its deactivated state, and is ready to participate in another action potential.
Na channel blockers-- > the substances that inhibit Na channel by binding in the:-
binds to EXTRAcellular side of the Na channel
---saxitoxin
---tetrodotoxin
binds to INTRAcellular side of the Na channel
--- Local anesthetics(hydrophobic)
---Class I antiarrhythmic agents
----phenytoin, carbamazepine
preference of binding to the 3 states of V.D. Na channel(active, inactive, and resting):
Local anesthetics--> inactive Na channel
class IA--> active
ClassIB--> Inactive
classIC--> all states: active, inactive, and resting
Phenytoin--> inactive Na channel
Which one binds to Na+ Channel keeping it open and Causes persistent Depolarization?
1. Ciguatoxin
2. Tetrodotoxin
3. Batrachotoxin
4. Saxitoxin
Answer
Ciguatoxin
Batrachotoxin
persistent Depolarization and eventually channel INACTIVATION.
-__________REPOLARIZATION phase of AP__________
Depolarization also closes the inactivation gates of the Na+ channel (but more slowly than it opens the activation gates). Closure of the inactivation gates results in closure of the Na+ channels, and the Na+ conductance returns toward zero.
Depolarization slowly opens K+ channels and increases K+ conductance to even higher levels than at rest.
The combined effect of closing the Na+ channels and greater opening of the K+ channels makes the K+ conductance higher than the Na+ conductance, and the membrane potential is repolarized. Thus, repolarization is caused by an outward K+ current.
__________Undershoot (hyperpolarizing afterpotential)__________
The K+ conductance remains higher than at rest for some time after closure of the Na+ channels. During this period, the membrane potential is driven very close to the K+ equilibrium potential.
The membrane potential is HYPERPOLARIZED below the RMP due to the prolonged opening of V.D. K channels
__________from hyperpolarizing to RMP__________
-the membrane potential is brought back from hyperpolarization to RMP by Na-K ATPase
__________B) properties of the action potential __________
__________ Refractory periods __________
1. Absolute refractory period (ARP)(functional refractory period)
is the period during which another action potential cannot be elicited, no matter how large the stimulus.
coincides with almost the entire duration of the action potential.
The length of this period determines the maximum FREQUENCY of action potentials. The shorter the ARP, the greater the maximum FREQUENCY
Explanation: Recall that the inactivation gates of the Na+ channel are closed when the membrane potential is depolarized. They remain closed until repolarization occurs. No action potential can occur until the INactivation gates open.
2. Relative refractory period
begins at the end of the absolute refractory period and continues until the membrane potential returns to the resting level.
An action potential can be elicited during this period only if a larger than usual inward current is provided.
Explanation: The K+ conductance is higher than at rest, and the membrane potential is closer to the K+ equilibrium potential and, therefore, farther from threshold; more inward current is required to bring the membrane to threshold.
3. Accommodation
occurs when the cell membrane is held at a depolarized level such that the threshold potential is passed without firing an action potential.
occurs because depolarization closes inactivation gates on the Na+ channels.
is demonstrated in hyperkalemia, in which skeletal muscle membranes are depolarized by the high serum K+ concentration. Although the membrane potential is closer to threshold, action potentials do not occur because inactivation gates on Na+ channels are closed by depolarization, causing muscle weakness.
__________C) Propagation of action potentials __________
o occurs by the spread of local currents to adjacent areas of membrane, which are then depolarized to threshold and generate action potentials.
o Conduction VELOCITY is increased by:
a.↑ fiber size(diameter). Increasing the diameter of a nerve fiber results in decreased internal resistance; thus, conduction velocity down the nerve is faster.
b. Myelination. Myelin acts as an insulator around nerve axons and increases conduction velocity. Myelinated nerves exhibit saltatory conduction because action potentials can be generated only at the nodes of Ranvier, where there are gaps in the myelin sheath (Figure 1-8). It is the nodes of Ranvier where voltage gated Na and K channels are concentrated. Demyelination (in GBS & MS) decreases the conduction velocity
http://i.imgur.com/d1mICTr.png
Figure shows Unmyelinated axon showing spread of depolarization by local current flow. Box shows active zone where action potential has reversed the polarity
… Figure 1-8 Myelinated axon. Action potentials can occur at nodes…
In a myelinated axon the the action potential is generated in each node of Ranvier (salutatory conduction). Between 2 nodes of ranvier, the impulse travels by local currents or electrotonic conduction. Thus, many of the same factors that govern the VELOCITY of electrotonic conduction also determine the SPEED of propagation of action potentials but remember that action potentials are all or none because it is regenerated in each node of ranvier. In this way an action potential remains the same size and shape as it is conducted
Describe the propagation in unmyelinated nerve.
1. One patch of membrane is depolarized to threshold and initiates AP
2. Current flows between depolarized patch of membrane and adjoining resting membrane.
3. Na channels are opened as once resting patch is depolarized to threshold. Ap is initiated in new patch.
4. AP is constantly regenerated in new patches of membrane as it is propagated.
What is the speed of propagation or conduction depend on?
Speed is determined by the membrane capacitance and electrical resistance of the axoplasm to the flow of current.
If you increase resistance or capacitance, speed will decrease.
If you increase diameter--> speed will increase.
It won't go backwards because of the refractory period.
What is saltatory conduction?
found in myelinated nerves.
AP only generate at nodes of Ranvier since voltage regulated Na channels only exist at nodes of Ranvier. AP flows between node to next node.
Does not waste time generating APs in membrane covered by myelin, therefore it is fast.
How does myelinated axon compare to that of an unmyelinated axon with the same diamter
myelinated would have a faster conduction velocity.
More on action [potential
- the size and shape of action potentials are not influenced by the size of the stimulus
- What is the duration of an action potential? 1 - 5 msec
-What is overshoot described as in the action potential generation? The point at which the membrane potential becomes positive
What is happening during repolarization? Na+ channels are inactivated and K+ are opened
-the voltage gated K+ channel has a single slow gate whereas voltage gated Na+ channel has both fast and slow gates
- What is the refractory period? The time when it is either impossible or more difficult to generate a second action potential
- What is absolute refractory? The period in which the voltage gated channels have not reset and therefore do not respond to stimulation
- What is relative refractory? This is during the period positive after potential in which the cell is hyperpolarized and is more difficult to generate a second potential
-What is voltage Inactivation? A cell membrane is maintained at a voltage potential above threshold and the voltage gated channels are not reset then action potentials can not be generated
-What is accomodation to slow depoalarization? This is what happens when a slow depolarizaion occurs which does not cause the voltage gated channels to respond and in turn does not produce an action potential
Describe key features of action potentials.
-long distance signal, can travel over many space constants
-spread is nondecremental fashion-stays the same size as spread
-threshold for generation of action potential. Small depolarizations do not reach threshold and dies away, if depolarization reaches threshold generate action potential which can spread down axon.
-it is an all or none principle-size of action potential DOES NOT depend on the size of the triggering stimulus.
What are the various stages of an action potential?
1. Cell rest, polarized-cell negative inside
2. Depolarization phage-sometimes called rising phase-due to opening of sodium channels (activation gate) Na rushes IN maintaining cell less negative
3. Overshoot-variable-where you actual make membrane potential positive, not all cells get this
4. Peak action potential
5. Repolarization phase-sometimes called falling phase-Na channel closes, K channel opens so K rushes OUT of the cell. Before the only thing holding K inside the cell was that it was negative inside bc K is in higher concentration inside the cell. Now that the inside of the cell is positive, there is both an electrical and chemical force pushing it out.
6. Hyperpolarization-sometimes called undershoot phase. K channels remain OPEN long enough, cell gets close to K Nernst potential.
Explain the concept of a threshold.
1. sufficient depolarization to trigger an AP
2. value of membrane potential at which inward flow of Na exceed the passive outward flow of K, so enter positive feedback cycle causing rapid depolarization.
3. Usually lowest at the initial segment of axon so that is where that AP is usually generated in most neurons
4. Initial segment of axon extends from axon hillock about 20 to 50 micrometers down the axon In myelinated axons initial segment and at the first segment of myelin sheath
5. In sensory neurons information is conveyed from peripheral sensory ending to the CNS. APs are first generated in the peripheral axon trigger zone and conducted towards the cell soma.
Do the Na or K concentration gradients change before or after an action potential?
No, they are identical before and after with K being higher inside the cell and Na being higher outside the cell. So few ions are needed to be moved to create an action potential, it does not change the overall concentration of the cell.
Here are questions related to this topic
Q__________Post valentine Action potential=====q1 to 30
Q___________action potential/RMP===============q31 to 41
Let me know if you see mistakes.
-most of the information here about membrane potential mainly refers to neurons
- The membrane potential is the electrical potential difference between the inside and outside of the cell across the cell membrane. It can be negative, zero or positive.
-let say the membrane is permeable only to one ion while impermeable to other ions and let say the concentration of that ion is higher on one side. Then as the ion diffuses due to its concentration gradient, it will generate a potential difference generated across the cell membrane called DIFFUSION POTENTIAL defined as the potential difference generated across the cell membrane because of concentration gradient of an ion. as the ion diffuses due to its concentration gradient, it will reach a diffusion potential at which the force due to concentration gradient is equal to the force due to electrical gradient so there is no net diffusion of the ion across the membrane. This diffusion potential is called the electrochemical EQUILIBRIUM POTENTIAL for that ion and it can be calculated by the NERNST EQUATION for that ion( E ion or ENa for ex) at a given concentration gradient of the ion
-If the membrane is permeable to more ions for ex to Na, K, Cl but not to negative charged proteins, the membrane potential can be calculated by using the GOLDMAN-hodgkin-Katz EQUATION, that takes in consideration electrochemical gradient and permeability of each ion
-ions can move through the cell membrane by: a) active transport via a pump for ex Na- K ATPase b) diffusion via ion channels of 3 types: 1) ungated or leaky channels so they are always open for ex K leaky channels or I funny sodium channels in SA node 2) ligand- gated channels, closed until they bind to the ligand 3) voltage gated channels, they are closed at RMP but open when the membrane potential reaches certain value. There are also mechanically-gated ion channels. In graded and action potential, the movement of ions through the cell membrane is by passive diffusion, not by active transport.
-Let see the different values of the membrane potential during 1) resting membrane potential 2) graded potential and 3) action potential
I) RESTING MEMBRANE POTENTIAL(RMP)
- in most neurons the typical measured resting membrane potential of −70 mV(values vary form different authors)
- What is the resting membrane potential for Nerves? Heart Pacemaker? Skeletal Muscle?
Nerves = -90mv Heart Pacemaker = -60mv Skeletal Muscle = -83 mv
-the value of the resting membrane potential (RMP) depends on 1) RMP mainly due to High K conductance and some Na conductance 2) Na- K pump 3) the donnan effect
- the RMP is mainly due to High K conductance and some Na conductance. The Nernst equation for chlorine is close to the RMP so it does not contribute to it. So the RMP can be calculated using the goldman equation that includes Na, K
-at rest the membrane is more permeable to K(via leaky channels) than Na so more K diffuses out so the RMP is negative and close to the Nernst equation of K. But the RMP is not equal to the Nernst equation of K because Na diffuses in, making it less negative than the Nernst equation of K.
-in the RMP, more than one ion contribute to the membrane potential across the plasma membrane (Vm) of a cell so RMP=Vm is calculated by GOLDMAN-hodgkin-Katz EQUATION
- When two or more ions contribute to the membrane potential across the plasma membrane (Vm) of a cell, it is likely that the membrane potential would not be at the equilibrium potential (E ion.) for any of the contributing ions. So no ion would be at its equilibrium (i.e., E ion not = Vm of RMP). For example, the resting membrane potential of a typical neuron is neither at the K+, Na+, nor Cl− equilibrium potential).For example the ENa not = Vm of RMP. This means that at the resting potential, Na+ is not at its electrochemical equilibrium and, thus, the chemical and electrical forces acting on Na are not equal.
- if the membrane potential is not exactly at the equilibrium potential for an ion, then an ELECTROCHEMICAL DRIVING FORCE(VDF) acts on the ion, causing the net movement of the ion across the membrane down its own electrochemical gradient( causes the ion to flow into or out of the cell). The driving force is quantified by the difference between the membrane potential and the ion equilibrium potential (VDF = Vm of RMP – E ion.). The driving force is the net ELECTROMOTIVE FORCE (EMF) that acts on the ion. The magnitude of the driving force indicates how far the membrane potential (Vm of RMP) is from the electrochemical equilibrium (E ion.) of an ion. Thus, the magnitude of the driving force indicates how far an ion is from its equilibrium. The arithmetic sign (i.e., positive or negative) of the driving force acting on an ion along with the knowledge of the valence of the ion (i.e., cation or anion) can be used to predict the direction of ion flow across the plasma membrane (i.e., into or out of the cell). Vm of RMP is calculated by using the Goldman-Hodgkin-Katz equation. E ion is calculated for each ion by using the Nernst equation.
-in the RMP, the rate at which an ion moves across a membrane depends on its NET FORCE or ELECTROCHEMICAL DRIVING FORCE(net EMF= VDF) and its conductance across the membrane. For ex Na has high EMF but low permeability.
-For chlorine, the measured Vm of RMP= is equal to the calculated E Cl- so chlorine is at its equilibrium, VDF=0 = Vm of RMP – E Cl. And so no matter what the membrane conductance to chlorine is, there will not be a net diffusion of chloride ions and a change in Cl membrane conductance will not result in net diffusion of chloride ions because VDF=0
-For potassium, the measured Vm of RMP= is NOT equal to the calculated E K- so K is NOT at its equilibrium, VDF== Vm of RMP – E K, VDF not=0, VDF is about 5mv, it is a small force so K is close to its electrochemical equilibrium. There are leaky or ungated K channel open at all times so there is net diffusion of K ions to the ouside of the membrane. Increasing K CONDUCTANCE will accelerate the efflux of K ions and hyperpolarize the cell. The K driving force can be changed by altering extracellular K concentration. INCREASING ECF K CONCENTRATION will decrease the net driving force of K (VDF== Vm of RMP – E K) -- > reduce the efflux of K ions or even create an efflux of K ions resulting in DEPOLARIZATION. On the other hand, DECREASING ECF K CONCENTRATION will increase the net driving force of K (VDF== Vm of RMP – E K) -- > increase the efflux of K ions resulting in HYPERPOLARIZATION. So the cell’s RMP is very sensitive to changes in the ECF K ion CONCENTRATION because the membrane PERMEABILITY of K at RMP is so much higher than of Na. that’s why hypokalemia or hyperkalemia result in cardiac electrical effects (and the pt dies before you see CNS electrical effects) while hyponatremia or hypernatremia does not affect the heart electrical activity but it affects the CNS due to CNS edema or shrinking resulting in seizures
If we have a higher than normal K permeability, what will happen to the membrane potential?
It will get closer to the Nerst potential of K, this will make the cell more negative, bc K is leaving the cell. Hyperpolarization.
At RMP an outward current is generated by a small amount of potassium ions leaking out of the cell through potassium-selective leak channels. This slow leak of positively charged potassium ions means that the internal cell membrane becomes slightly negatively charged compared to the outside; this gives rise to the negative resting membrane potential, which for neurons is around -70 mV.
-For sodium, the measured Vm of RMP= is NOT equal to the calculated E Na- so Na is NOT at its equilibrium, VDF== Vm of RMP – E Na, VDF not=0, VDF is about 135mv, it is a large force so Na is very far away from its electrochemical equilibrium. In resting conditions there is not a significant number of open Na channels so at RMP the Na CONDUCTANCE is close to zero. So at RMP even though the Na driving force is high, the influx of Na is very low due to the very low Na conductance at RMP. Increasing Na CONDUCTANCE will increase the influx of Na ions, resulting in DEPOLARIZATION. Because Na channels are closed under resting conditions, change in ECF Na CONCENTRATION will not affect the resting membrane potential. So the cell’s RMP is NOT sensitive to changes in the ECF Na ion CONCENTRATION because the membrane PERMEABILITY of Na at RMP is very low. that’s why hyponatremia or hypernatremia does not affect the heart electrical activity but it affects the CNS due to CNS edema or shrinking resulting in seizures
Does threshold generation depend on calcium?
When EC concentration of Ca is lowered what happens to the probability that a Na channel will be opened at any voltage?
It is increased
A smaller than normal amount of depolarization will bring an excitable membrane to its firing threshold.
Hypocalcemia causes an increase in neuromuscular irritability...hypocalcemic tetany, laryngospasms can cause respiratory failure.
If EC concentration of Ca is raised, what happens to the probability that a Na channel will be opened at a certain voltage?
It will be decreased.
Can shift excitable membrane threshold so that a larger amount of depolarization is needed to bring membrane to the firing level.
Causes decrease in neuromuscular irritability-fatigue, lethargy, muscle weakness and diminished reflexes, mental confusion.
1a Maintenance of the Resting Membrane Potential in STEADY STATE
-GENESIS of the RMP is mainly due to High K conductance and some Na conductance. MAINTENANCE of the RMP is mainly due to Na- K pump
-the value of the resting membrane potential (RMP)depends are 1) RMP mainly due to High K conductance and some Na conductance 2) Na- K pump(5-10% of RMP) 3) the donnan effect(small % of RMP)
__________ Na- K pump________
- Na- K pump has two functions: 1) In small amount the Na- K pump directly contributes to the RMP( 5-10% of the RMP, direct ELECTROGENIC contribution of the pump) by pumping out a net 1 positive charge(3Na out-2K in=1Na out) making the membrane more negative inside 2) maintenance of the Na and K concentration gradients so the Na-K contributes indirectly to the RMP.
-The Na-K pump maintains constant the Na and K concentration gradients in a STEADY STATE. In steady state free energy is required to maintain the constant resting membrane potential and ionic gradient. In DONNAN EQULIBRIUM no free energy is required
- Since in most cells Vm of RMP is not at the equilibrium potential for either K+, or Na+, at the resting membrane potential, each ion is moving down its own electrochemical gradient according to the driving force acting on the ion. Thus, it is clear that under resting physiological conditions, there is constant efflux of K+ from the cell, influx of Na+ into the cell. Therefore, if the ionic concentration gradients are not maintained, in the long run, because of the constant ionic fluxes across the plasma membrane, the concentration gradients will be DISSIPATED. Cells avoid this situation by having a primary active transporter (i.e., pump) which pumps Na+ out of the cell and K+ into the cell to counteract the constant movements of these two ions down their electrochemical gradients. This protein is the Na+/K+ ATPase which couples the hydrolysis of one ATP molecule to moving 3 Na+ ions out of the cell and 2 K+ ions into the cell.
--To maintain the concentration gradients for Na+ and K+, it is necessary to transport Na+ out of the cell and K+ back into the cell. The Na+/K+-ATPase performs this function. This pump is essential for the maintenance of Na+ and K+ concentrations across the membrane. If this pump stops working (as occurs under anoxic conditions when ATP is lost), or if the activity of the pump is inhibited (as occurs with cardiac glycosides such as digitalis, ouabain), Na+ accumulates within the cell and intracellular K+ falls. This causes DEPOLARIZATION of the resting membrane potential. Furthermore, it is important to note that this pump is electrogenic in nature because it extrudes 3 Na+ for every 2 K+ entering the cell. By pumping more positive changes out of the cell than into the cell, the pump activity creates a negative potential within the cell. This potential may be up to -10 mV. Inhibition of this pump, therefore, causes depolarization resulting not only from changes in Na+ and K+ concentration gradients, but also from the loss of an electrogenic component of the membrane potential.
-If the activity of the Na+/K+ ATPase is inhibited in a cell (for example with ouabain) initially the membrane potential is not altered (or is altered very slightly). However, if the pump is not allowed to function for a long period of time (> tens of seconds), the membrane potential begins to become less negative until it ultimately completely disappears (i.e., Vm = 0 i.e. it will be halfway between the Na and K Nernst equilibrium potentials, which is approximately 0). This is because constant Na+ influx into the cell and K+ efflux out of the cell serve to decrease the transmembrane Na+ and K+ concentration gradients leading to a membrane potential of close to zero or the average of the Nernst potential of K and Na. Thus, in order to maintain the membrane potential, cells have to expend energy to maintain the proper intracellular Na+ and K+ concentrations. Therefore, although the Na+/K+ ATPase is not responsible for the generation of the membrane potential, it is responsible for its maintenance by maintaining the normal intracellular K+ and Na+ concentrations.
At this point, it may be wondered what maintains the extracellular concentrations of K+ and Na+. The kidneys are responsible for maintaining the low extracellular K+ concentration and the high extracellular Na+ concentration. The kidneys (urinary system) working in conjunction with the endocrine system are responsible for extracellular K+ and Na+ homeostasis.
--after an action potential, the membrane potential is brought back from hyperpolarization to RMP by Na-K ATPase
---after an EPSP graded potential, the membrane potential is brought back from the subthreshold depolarization to RMP by Na-K ATPase
---after an IPSP graded potential, the membrane potential is brought back from the hyperpolarization to RMP by Na-K ATPase
What would happen if all the Na/K ATPases were poisoned with Ouabain in an axon? Would the action potential immediately stop?
Blocking the sodium potassium pump leads to a gradual influx of sodium into the cell, and efflux of potassium out of the cell. These changes in concentration lead to a change in the equilibrium potential for potassium, as well as for sodium. As the equilibrium potential for potassium becomes more positive, the resting membrane potential becomes more positive (i.e., more DEPOLARIZED). Because of the sodium influx into the cell, the equilibrium potential for sodium is changed, namely, it is less positive. And because the peak amplitude of the action potential is dependent upon the value of the sodium equilibrium potential, the peak amplitude of the action potential would also decrease over time.
Initially the Nerve cell can fire thousands of action potentials even if Na/K pump is poisoned bc only relatively few ions are needed to move in or out of the cell to change membrane potential. Ion gradients would slowly disappear though resulting in decrease frequency and amplitude of action potentials. Once ion gradients are disturbed enough, there are no more action potentials.
__________ouabain and digoxin (Cardiac glycosides) __________
Drugs such as ouabain and digoxin are cardiac glycosides. Digoxin from the foxglove plant is used clinically, whereas ouabain is used only experimentally due to its extremely high potency.
Normally, sodium-potassium pumps in the membrane of cells (in this case, cardiac myocytes) pump potassium ions in and sodium ions out. Cardiac glycosides inhibit this pump by stabilizing it in the E2-P transition state, so that sodium cannot be extruded: intracellular sodium concentration therefore increases. A second membrane ion exchanger, NCX, is responsible for 'pumping' calcium ions out of the cell and sodium ions in (3Na/Ca); raised intracellular sodium levels inhibit this pump, so calcium ions are not extruded and will also begin to build up inside the cell.
Increased cytoplasmic calcium concentrations cause increased calcium uptake into the sarcoplasmic reticulum via the SERCA2 transporter. Raised calcium stores in the SR allow for greater calcium release on stimulation, so the myocyte can achieve faster and more powerful contraction by cross-bridge cycling. The refractory period of the AV node is increased, so cardiac glycosides also function to regulate heart rate.
Binding of cardiac glycoside to Na-K ATPase is slow, and also, after binding, intracellular calcium increases gradually. Thus, the action of digitalis (even on IV injection) is delayed.
Raised extracellular potassium decreases binding of cardiac glycoside to Na-K ATPase. As a consequence, increased toxicity of these drugs is observed in the presence of Hypokalemia.
If SR calcium stores become too high, some ions are released spontaneously through SR ryanodine receptors. This effect leads initially to bigeminy: regular ectopic beats following each ventricular contraction. If higher glycoside doses are given, rhythm is lost and ventricular tachycardia ensues, followed by fibrillation.
__________Donnan Effect__________
- the donnan effect also contributes to the RMP by maintaining the diffusion gradient for K. The RMP is at steady state but not at donnan equilibrium.
When an ion on one side of a membrane cannot diffuse through the membrane, the distribution of other ions to which the membrane is permeable is affected in a predictable way. For example, the negative charge of a nondiffusible anion hinders diffusion of the diffusible cations and favors diffusion of the diffusible anions. Donnan and Gibbs showed that in the presence of a nondiffusible ion, the diffusible ions distribute themselves so that at equilibrium their concentration ratios are equal: the Gibbs–Donnan equation. It holds for any pair of cations and anions of the same valence.
The Donnan effect on the distribution of ions : because of charged proteins (Prot–) in cells, there are more osmotically active particles in cells than in interstitial fluid, and because cells have flexible walls, osmosis would make them swell and eventually rupture if it were not for Na, K ATPase pumping ions back out of cells. Thus, normal cell volume and pressure depend on Na, K ATPase.
II) GRADED POTENTIAL
A graded potential is local(travels in small regions of the plasma membrane), a graded(refers to the magnitude of the potential change) response to a stimulus. They are subthreshold. These graded potentials "add" together (exhibit spatial and temporal summation ) and if the membrane potential if it becomes large enough to reach the threshold it produces an action potential.
http://i.imgur.com/gVO3WG9.png
in this image, a,b,c are subthreshold graded potential and do NOT trigger action potential, while d is a graded potential that reaches threshold and triggers action potential
Graded potential is a depolarization or hyperpolarization of a neuron that varies in amplitude.
An action potential is not graded and is all or nothing.
-Graded potentials generates local current. Graded potential propagate by local current or electrotonic conduction. In neurons the graded potentials are generated in the dendrites or soma and then travel by local current or electrotonic conduction to the first node of ranvier , located close to the AXON HILLOCK, where the action potential will be generated, i.e. the graded potential will bring the membrane potential in the axon hillock to threshold and here VOLTAGE GATED sodium channels will open to generate the action potential. The initial segment of the axon(near axon hillock) is rich in VOLTAGE GATED sodium channels. Dendrites have few voltage-gated sodium channels. As such the capability of these structures in generating action potentials is extremely limited. Therefore, the transmission of the electrical signal in the dendrite is via a non action potential mechanism, electrotonic conduction.
So from dendrites and soma up to the initial segment of the axon the impulse travels by graded potential. From the axon hillock to the axon terminal and synapse the impulse travels by action potential
-Graded potentials are conducted with decrement. i.e. the amplitude or magnitude falls off the further you get from the point of origin. Decrement think DECREASE. They decrease in magnitude the further they get from the origin. Why does decrement occur in graded potentials? Because charges are lost across the membrane because of “leaky” channels as the graded potential is conducted and the magnitude of the membrane potential decreases with distance from the site of origin(charge density falls)
How far can a graded potential travel? 1-2mm of the origin. Graded potentials die out in 1-2mm of the origin
-Graded potential and the local current they generate can function as signals over very short distances and some cells use to transmit signals only by generating graded potentials without generating action potential for ex bipolar cells of the retina generate graded potential but not action potential.
- Graded potentials serve as the only communication in some neurons.
__________Algebraic summation of graded potentials__________
Graded potentials are subject to summation, spatially and/or temporally.
Spatial summation: If a cell is receiving SIMULTANEOUSLY 2 or more inputs at synapses that are near each other, their postsynaptic potentials add together. If the cell is receiving two excitatory postsynaptic potentials, they combine so that the membrane potential is depolarized by the sum of the two changes. If there are two inhibitory potentials, they also sum, and the membrane is hyperpolarized by that amount. If the cell is receiving both inhibitory and excitatory postsynaptic potentials, they can cancel out, or one can be stronger than the other, and the membrane potential will change by the difference between them.
Temporal summation: When a cell receives inputs that are close together in time(separated in TIME), they are also added together, even if from the same synapse. Thus, if a neuron receives an excitatory postsynaptic potential, and then the presynaptic neuron fires again, creating another EPSP, then the membrane of the postsynaptic cell is depolarized by the total of the EPSPs.
_______________Conduction of graded potential_______________
-graded potential is conducted from one point of the membrane to the next point by ELECTROTONIC CONDUCTION or LOCAL CURRENTS, i.e. without crossing the membrane the ions move from high potential difference to low potential difference(from depolarized area to undepolarized area inside the membrane and viceversa in the outside of the membrane). A local current flow shows SPACE (LENGTH) CONSTANT and TIME CONSTANT
http://i.imgur.com/obCqaMG.png
the image shows mechanism of electrotonic spread of depolarization. A, The reversal of membrane polarity that occurs with local depolarization. B, The local currents that flow to depolarize adjacent areas of the membrane and allow conduction of the depolarization
What is the space constant or Length constant?
A way to prove that through distance, the voltage gets smaller. After one space constant it is 37% of the maximum voltage(membrane potential)(it is decayed by 63% from its peak value ) .
Is the distance between the injection site of a current at one point of an axon and the point where the steady state transmembrane voltage change has decayed by 63% from its peak value.
Local potentials (graded potentials)would decrease to almost nothing after several length constants. Local potential traveling down an axon dies away bc some current is leaking out across the membrane resistance (Rm).
- The magnitude of the potential change decreases exponentially with distance from the site of origin. The distance over which the potential change decreases to 1/e (37%) of its maximal value is called the length constant or space constant (e is the base of natural logarithms and is equal to 2.7182). A length constant of 1 to 3 mm is typical for mammalian axons
-Length constant is defined as the distance in which a change in membrane potential declines to 37% of the initial value. Thicker processes like dendrites have higher length constants which helps in passive conduction and contributes to spatial summation. Axons are thinner and have smaller length constants, this is why they need active conduction (via APs) to provide repetitive amplification of the potential change along its length.
What is the time constant?
The amount of time it takes for a voltage to change by a certain percentage (63%) of the eventual new stead state value. This shows that signals go away fast.
Current from a cell membrane does not immediately change membrane potential bc the cell membrane acts as a capacitor.
This is like RC circuits. The time constant is a function of an axon's electrical resistance and capacitance.
t=RC
Takes time to charge and discharge.
http://o.quizlet.com/i/wbI8jj5AOAh0eqoiG4_xgA.jpg
Time constant: (tau) time it takes to charge the membrane to 63% of the final membrane potential. It is a function of membrane resistance X membrane capacitance. Basically, the higher the time constant, the slower the membrane changes voltage. Dendrites and soma have high time constants which contributes to temporal summation of synaptic activity
MS decrease in Space constant
MS INcrease in Time constant
What is membrane capacitance?
the ability of a membrane to maintain separate charges
__________Types of graded potentials__________
There are 4 types of graded potentials. They are the end plate potential(EPP and MEPP), pacemaker potential, generator potentials or receptor potentials and post synaptic membrane potential(PSP like IPSP or EPSP).
__________a) Generator (Receptor) potential__________
-sensory receptors (ex mechanoreceptors, thermoreceptors, nociceptors, chemoreceptors[ex taste buds] and electromagnetic receptors[vision]) respond to stimuli by generating graded potential called generator potential or receptor potential
-Receptor potential, a type of graded potential, is the transmembrane potential difference of a sensory receptor
-A receptor potential is often produced by sensory transduction. It is generally a depolarizing event resulting from inward current flow(exception, light in photoreceptors causes hyperpolarization). The influx of current will often bring the membrane potential of the sensory receptor towards the threshold for triggering an action potential.
-if the graded potential reaches a threshold and an action potential is generated and the sensory information is sent to the spinal cord and brain
-for example a light touch is detected by Meissner corpuscles, receptors in the skin. Many of these are found next to hair follicles so even if the skin is not touched directly, movement of the hair is detected. The light movement of a hair opens mechanically-gated sodium channels producing a generator potential. Deforming the corpuscle creates a generator potential in the sensory neuron arising within it. This is a graded response: the greater the deformation, the greater the generator potential. If the generator potential reaches threshold, voltage-gated sodium channels are opened that triggers an action potential at the first node of Ranvier of the sensory neuron. Once threshold is reached, the magnitude of the stimulus is encoded in the frequency of impulses generated in the neuron. So the more massive or rapid the deformation of a single corpuscle, the higher the frequency of nerve impulses generated in its neuron.
-So the mechanically-gated sodium channels producing a generator potential while the voltage-gated sodium channels generate an action potential
__________b) Pacemaker potential__________
-The SA node has Leaky Na I funny Channels that generate graded potential causing slow depolarization of the cell toward the threshold(phase 4) and then opening of voltage-gated Ca2+ channels generate the action potential(phase 0)
-graded potential is responsible for cardiac automaticity
__________c) Postsynaptic potential__________
-Postsynaptic membrane potentials are graded potentials generated in the postsynaptic membrane during synaptic transmission. Postsynaptic potentials are changes in the membrane potential of the postsynaptic terminal of a chemical synapse.
-They are caused by the presynaptic neuron releasing neurotransmitters from the terminal bouton at the end of an axon into the synaptic cleft. The neurotransmitters bind to receptors on the postsynaptic neuron and many of these receptors contain an ion channel [ligand-gated ion channel or ionotropic receptors] that opens upon binding of the neurtransmitter and allow of passing positively or negatively charged ions either into or out of the cell.
--Postsynaptic potentials can be excitatory postsynaptic potential (EPSP) orinhibitory postsynaptic potential (IPSP),
Excitatory Postsynaptic Potential (EPSP)
Usually Na or Ca moving down their concentration gradients causing depolarization
Inhibitory Postsynaptic Potential (IPSP)
movement of Cl and K down their concentration gradients causing hyperpolarization
____________________Excitatory postsynaptic potential_____________
-If the opening of the ion channel results in a net gain of positive charge across the membrane, the membrane is said to be depolarized, as the potential comes closer to zero. This is an excitatory postsynaptic potential (EPSP), as it brings the neuron's potential closer to its firing threshold (about -50mV). For example acetylcholine
-an excitatory postsynaptic potential (EPSP) is a temporary depolarization of postsynaptic membrane potential caused by the flow of positively charged ions into the postsynaptic cell as a result of opening of ligand-gated ion channels. EPSPs can also result from a decrease in outgoing positive charges.
-EPSPs, like IPSPs, are graded (i.e. they have an additive effect). When multiple EPSPs occur on a single patch of postsynaptic membrane, their combined effect is the sum of the individual EPSPs. Larger EPSPs result in greater membrane depolarization and that brings the membrane potential upto the threshold and opening of voltage gated sodium channels to start firing an action potential.
-When an active presynaptic cell releases neurotransmitters into the synapse, some of them bind to receptors on the postsynaptic cell. These receptors contain an ion channel capable of passing positively charged ions into the cell (at excitatory synapses, the ion channel typically allows SODIUM into the cell, generating an excitatory postsynaptic current). This depolarizing current causes an increase in membrane potential, the EPSP.
-The neurotransmitter most often associated with EPSPs is the amino acid glutamate, and is the main excitatory neurotransmitter in the central nervous system.
____________________ Inhibitory postsynaptic potential______________
-If the opening of the ion channel results in a net gain of negative charge, this moves the potential further from zero and is referred to as hyperpolarization. This is an inhibitory postsynaptic potential (IPSP), as it changes the charge across the membrane to be further from the firing threshold. inhibitory postsynaptic potentials (IPSPs) usually result from the flow of negative ions into the cell or positive ions out of the cell.
Some common neurotransmitters involved in IPSPs are GABA and glycine that bind their receptors and result in increased entry of chloride into cells . GABA binds to GABAA receptors that are ion channels. GABA is the most common neurotransmitter associated with IPSPs in the brain.
This system[1] IPSPs can be temporally summed with subthreshold or suprathreshold EPSPs to reduce the amplitude of the resultant postsynaptic potential. Equivalent EPSPs (positive) and IPSPs (negative) can cancel each other out when summed. The balance between EPSPs and IPSPs is very important in the integration of electrical information produced by inhibitory and excitatory synapses.
Neurotransmitters are not inherently excitatory or inhibitory: different receptors for the same neurotransmitter may open different types of ion channels.
__________d) End-plate potential__________
-In the neuromuscular junction of vertebrates, EPP (end-plate potentials) are mediated by the neurotransmitter acetylcholine, which is also the main transmitter in the central nervous system of invertebrates.[citation needed]
-End-plate potentials are graded potentials that develop at the postsynaptic end-plate membrane in the neuromuscular junction. They are always stimulatory(depolarization)
-End plate potentials (EPPs) are the depolarizations of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction. They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucer-like appearance.
-When an action potential reaches the axon terminal of a motor neuron, depolarization of the presynaptic terminal opens Ca channels, Calcium rushes causes the synaptic vesicles carrying acetylcholine to fuse with the PM and empty their contents into the cleft(NMJ) by exocytosis. Acetylcholine binds into nicotinic acetylcholine receptors which is also Na and K ion channel. Because the ligand-gated channel conducts both Na and K ions, the postsynaptic membrane is depolarized halfway between the Na and K nernest equilibrium potentials(approximately 0)
-A skeletal muscle action potential is generated when the motor endplate potential is sufficient to raise the surrounding sarcolemmal potential above the threshold for activation of the VOLTAGE GATED Na+ channels that are abundant throughout the sarcolemma. When these channels are activated, the membrane is rapidly depolarized towards the Nernst potential for Na+ (Table 1). However, the peak potential achieved is approximately +30 mV. The Nernst potential is not achieved for two main reasons. First, just as the Na+ channels are activated by membrane voltage changes, a process of inactivation is also initiated as the membrane potential becomes less negative. Inactivation is a slower mechanism than activation, so the Na+ current continues to flow for a short period after the onset of inactivation, but not sufficiently to reach the Nernst potential. The second factor limiting the upstroke of the action potential is the voltage activation of rectifying potassium channels. Their activation is initiated also during the upstroke of the action potential but (in a similar way to Na+ channel inactivation) there is a slight delay in channel opening. The resulting K+ current, in addition to limiting the peak of the action potential, is also principally responsible for repolarization.
Once an action potential has been generated, it spreads as a wave over the sarcolemma. Skeletal muscle sarcolemma is characterized by invaginations called transverse- or T-tubules that run perpendicular to the surface of the cell deep into its body. By passing down the t-tubular membrane, the action potential is carried to the structures responsible for transducing an electrical into a chemical signal that will trigger activation of the contractile elements. Depolarization of the T-tubules causes a conformational change in its dihydydropyridine receptor, which opens Ca release channels(RYNODINE receptors) in the nearby SR, causing the release of Ca from the sarcoplasmatic reticulum. Then the intracellular calcium binds to troponin C, etc
-the acetylcholine contained in ONE synaptic vesicle(quantum) produces a MINIATURE End plate potential (MEPP), the smallest possible EPP. MEPP is less than 1mV in amplitude and not enough to reach threshold. MEPPs summate to produce a suprathreshold EPP that can depolarize the membrane potential up to the threshold and open voltage gated Na channels to result in action potential of the muscle cell
_______________Clinical applications___________
-Lambert-Eaton myasthenic syndrome(LEMS) and botulism cause Dysfunction in quantal Ca-mediated synaptic vesicle release mechanism to produce EPP but no effect on MEPP (because a synaptic vesicle can be releases SPONTANEOUSLY, without Calcium mediated, and produce MEPP)
-LEMS decreases vesicles exocytosis resulting in: decrease EPP, NRL MEPP
-BOTULIN toxin causes total blockade of vesicles exocytosis resulting in: no EPP(EPP=MEPP), NRL MEPP. Botulinum toxin produced by the bacteria Clostridium botulinum is the most powerful toxic protein. It prevents release of acetylcholine at the neuromuscular junction by inhibiting DOCKING of the neurotransmitter vesicles.
- Myasthenia Gravis(MG)-- antibodies directed against the AChR- -> fewer AChRs are opened by each quantum of ACh release, and the amplitude of the MEPP is reduced. Fewer MEPPs are generated and the EPP is lower.
- Alpha-latrotoxin, a large protein toxin, found in black widow spiders causes pokes in the PM and destabilizes cell membranes by opening (acts as) Calcium channels resulting in a massive influx of calcium at the axon terminal causing massive exocytosis of acetylcholine and norepinephrine from nerve terminals, depleting its stores of acetylcholine from presynaptic nerve terminals.. This causes HYPOCALCEMIA and tetany. Clinically,Black widow spider causes painful muscle spasms with severe abdominal pain,, hypocalcaemia and tetany, followed by weakness. The treatment is Calcium gluconate and Black widow spider (Latrodectus mactans) antivenom called lexicomp
- curare acts post-synaptically, it compettitvely inhibits acetylchole from binding to its nicotinic ACh receptors in the NMJ. Curare is a classic antagonist of nicotinic AChRs and competes with acetylcholine for the binding site, which is effective as a neuromuscular blocking agent (nondepolarizing blocker) for general anesthesia.
Curare decreases the AMPLITUDE of both MEPPs and EPPs but NORMAL FREQUENCY of both MEPPs and EPPs
Curare is a competitive inhibitor of ACh, hence it will inhibit or reduce the amplitude of the miniature end-plate potential. Since curare affects the amplitude of the miniature end-plate potential, it would also affect the amplitude of the end-plate potential through the same mechanisms, competitive inhibition of ACh for its receptor.
Curare effects the ACh receptors on the postsynaptic side of the synapse. Hence, it will have no effect on the release of transmitter from the presynaptic terminal.
The frequency of MEPPs would not be affected. The frequency of MEPPs is determined strictly by the levels of basal calcium in the presynaptic terminal. Curare is a competitive antagonist of ACh, hence it would affect the amplitude of the miniature end-plate potential, but not the frequency.
__________________Graded Potentials versus Action Potentials_________________
GRADED potential: its amplitude is proportional to stimulus strength, exhibits summation, conduction is decremental with distance, not propagated
ACTION potential: its amplitude is independent of stimulus strength(all or none), does not exhibit summation, conduction is non-decremental with distance, propagated unchanged in magnitude
http://i.imgur.com/h9xf0j4.png
here in the image only the green color graded potential reaches threshold to initiate action potential
III) ACTION POTENTIAL(AP)
-Action potential is a property of excitable cells (i.e., nerve, muscle) that consists of a rapid depolarization, or upstroke, followed by repolarization of the membrane potential. Action potentials have stereotypical size and shape, are propagating, and are all-or-none.
http://i.imgur.com/xX73Lvs.png
figure shows APs in 3 different tissues
__________A) Phases of the action potential __________
Here is the SEQUENCE of an action potential in a nutshell
1. RMP due to leaky ungated K channels
2. GRADED potential is generated by ligand or mechanical gated ion channel
3. threshold voltage is reached
4. V.D. Na+ gates begin to open(opening of activation gate)-- > DEPOLARIZATION
5. V.D. K+ gates begin to open
6. Na+ gates begin to close
7. membrane REPOLARIZATION begins and continues up to HYPERPOLARIZATION
8. V.D. K+ gates close
9. Membrane potential is brought from hyperpolarization to RMP by Na-K ATPase
-__________the resting membrane potential(RMP )__________
is approximately −70 mV, cell negative.
is the result of the high resting conductance to K+, which drives the membrane potential toward the K+ equilibrium potential.
The high resting conductance to K+ is due to the ungated leaky K channels
At rest, the Na+ channels are closed and Na+ conductance is low.
-at RMP, all voltage gated Na and K channels are CLOSED
-__________from RMP to threshold__________
-a GRADED potential will bring the RMP to the threshold by opening LIGAND GATED or mechanically-gated ion channels.
- Threshold is the membrane potential at which the action potential is inevitable. At threshold potential, net inward current becomes larger than net outward current. The resulting depolarization becomes self-sustaining and gives rise to the upstroke of the action potential. If net inward current is less than net outward current, no action potential will occur (i.e., all-or-none response).
http://i.imgur.com/F0oocxD.png
__________DEPOLARIZATION(from threshold to upstroke)__________
2. Upstroke of the action potential
1. depolarization of the the membrane potential to threshold causes rapid opening of the activation gates of the voltage gated Na+ channel, and the Na+ conductance of the membrane promptly increases.
2. The Na+ conductance becomes higher than the K+ conductance, and the membrane potential is driven toward (but does not quite reach) the Na+ equilibrium potential of +65 mV. Thus, the rapid depolarization during the upstroke is caused by an inward Na+ current.
3. The overshoot is the brief portion at the peak of the action potential when the membrane potential is positive. However, the peak potential achieved is approximately +30 mV. The Nernst equilibrium potential of sodium is not achieved for two main reasons. First, just as the Na+ channels are activated by membrane voltage changes, a process of inactivation is also initiated as the membrane potential becomes less negative. Inactivation is a slower mechanism than activation, so the Na+ current continues to flow for a short period after the onset of inactivation, but not sufficiently to reach the Nernst potential. The second factor limiting the upstroke of the action potential is the voltage activation of rectifying POTASIUM channels. Their activation is initiated also during the upstroke of the action potential but (in a similar way to Na+ channel inactivation) there is a slight delay in channel opening. The resulting K+ current, in addition to limiting the peak of the action potential, is also principally responsible for repolarization.
4. Tetrodotoxin (TTX) and lidocaine block these voltage-sensitive Na+ channels and abolish action potentials.
- Tetrodotoxin is a poison found in the certain poisonous fishes such as pufferfish and triggerfish which blocks the VOLTAGE-GATED sodium ion channels, impacting both the initiation and the propagation of action potentials in the motor neuron.
Local anesthetics are hydrophobic molecules that bind to voltage-sensitive Na+ channels, inhibiting sodium transport and, consequently, also the action potential responsible for the nerve impulse.
Internal block of axonal voltage-gated sodium channels: Local anaesthetic drugs, such as lidocaine, cross the membrane lipid bilayer to enter the cell where they become polarised. The polar form of the drug is more readily able to block the voltage-gated sodium channel in its active state - this is called state dependent block.
Voltage-gated Na+ channels can exist in any of three distinct states: deactivated (closed), activated (open), or inactivated (closed).
-At the peak of the action potential, when enough Na+ has entered the neuron and the membrane's potential has become high enough, the Na+ channels inactivate themselves by closing their inactivation gates. once they are inactivated (closed), they will not respond to a second stimuli until the membrane potential repolarizes to the RMP
- When the membrane's voltage becomes low enough, the inactivation gate reopens and the activation gate closes in a process called deinactivation, or removal of inactivation. With the activation gate closed and the inactivation gate open, the Na+ channel is once again in its deactivated state, and is ready to participate in another action potential.
Na channel blockers-- > the substances that inhibit Na channel by binding in the:-
binds to EXTRAcellular side of the Na channel
---saxitoxin
---tetrodotoxin
binds to INTRAcellular side of the Na channel
--- Local anesthetics(hydrophobic)
---Class I antiarrhythmic agents
----phenytoin, carbamazepine
preference of binding to the 3 states of V.D. Na channel(active, inactive, and resting):
Local anesthetics--> inactive Na channel
class IA--> active
ClassIB--> Inactive
classIC--> all states: active, inactive, and resting
Phenytoin--> inactive Na channel
Which one binds to Na+ Channel keeping it open and Causes persistent Depolarization?
1. Ciguatoxin
2. Tetrodotoxin
3. Batrachotoxin
4. Saxitoxin
Answer
Ciguatoxin
Batrachotoxin
persistent Depolarization and eventually channel INACTIVATION.
-__________REPOLARIZATION phase of AP__________
Depolarization also closes the inactivation gates of the Na+ channel (but more slowly than it opens the activation gates). Closure of the inactivation gates results in closure of the Na+ channels, and the Na+ conductance returns toward zero.
Depolarization slowly opens K+ channels and increases K+ conductance to even higher levels than at rest.
The combined effect of closing the Na+ channels and greater opening of the K+ channels makes the K+ conductance higher than the Na+ conductance, and the membrane potential is repolarized. Thus, repolarization is caused by an outward K+ current.
__________Undershoot (hyperpolarizing afterpotential)__________
The K+ conductance remains higher than at rest for some time after closure of the Na+ channels. During this period, the membrane potential is driven very close to the K+ equilibrium potential.
The membrane potential is HYPERPOLARIZED below the RMP due to the prolonged opening of V.D. K channels
__________from hyperpolarizing to RMP__________
-the membrane potential is brought back from hyperpolarization to RMP by Na-K ATPase
__________B) properties of the action potential __________
__________ Refractory periods __________
1. Absolute refractory period (ARP)(functional refractory period)
is the period during which another action potential cannot be elicited, no matter how large the stimulus.
coincides with almost the entire duration of the action potential.
The length of this period determines the maximum FREQUENCY of action potentials. The shorter the ARP, the greater the maximum FREQUENCY
Explanation: Recall that the inactivation gates of the Na+ channel are closed when the membrane potential is depolarized. They remain closed until repolarization occurs. No action potential can occur until the INactivation gates open.
2. Relative refractory period
begins at the end of the absolute refractory period and continues until the membrane potential returns to the resting level.
An action potential can be elicited during this period only if a larger than usual inward current is provided.
Explanation: The K+ conductance is higher than at rest, and the membrane potential is closer to the K+ equilibrium potential and, therefore, farther from threshold; more inward current is required to bring the membrane to threshold.
3. Accommodation
occurs when the cell membrane is held at a depolarized level such that the threshold potential is passed without firing an action potential.
occurs because depolarization closes inactivation gates on the Na+ channels.
is demonstrated in hyperkalemia, in which skeletal muscle membranes are depolarized by the high serum K+ concentration. Although the membrane potential is closer to threshold, action potentials do not occur because inactivation gates on Na+ channels are closed by depolarization, causing muscle weakness.
__________C) Propagation of action potentials __________
o occurs by the spread of local currents to adjacent areas of membrane, which are then depolarized to threshold and generate action potentials.
o Conduction VELOCITY is increased by:
a.↑ fiber size(diameter). Increasing the diameter of a nerve fiber results in decreased internal resistance; thus, conduction velocity down the nerve is faster.
b. Myelination. Myelin acts as an insulator around nerve axons and increases conduction velocity. Myelinated nerves exhibit saltatory conduction because action potentials can be generated only at the nodes of Ranvier, where there are gaps in the myelin sheath (Figure 1-8). It is the nodes of Ranvier where voltage gated Na and K channels are concentrated. Demyelination (in GBS & MS) decreases the conduction velocity
http://i.imgur.com/d1mICTr.png
Figure shows Unmyelinated axon showing spread of depolarization by local current flow. Box shows active zone where action potential has reversed the polarity
… Figure 1-8 Myelinated axon. Action potentials can occur at nodes…
In a myelinated axon the the action potential is generated in each node of Ranvier (salutatory conduction). Between 2 nodes of ranvier, the impulse travels by local currents or electrotonic conduction. Thus, many of the same factors that govern the VELOCITY of electrotonic conduction also determine the SPEED of propagation of action potentials but remember that action potentials are all or none because it is regenerated in each node of ranvier. In this way an action potential remains the same size and shape as it is conducted
Describe the propagation in unmyelinated nerve.
1. One patch of membrane is depolarized to threshold and initiates AP
2. Current flows between depolarized patch of membrane and adjoining resting membrane.
3. Na channels are opened as once resting patch is depolarized to threshold. Ap is initiated in new patch.
4. AP is constantly regenerated in new patches of membrane as it is propagated.
What is the speed of propagation or conduction depend on?
Speed is determined by the membrane capacitance and electrical resistance of the axoplasm to the flow of current.
If you increase resistance or capacitance, speed will decrease.
If you increase diameter--> speed will increase.
It won't go backwards because of the refractory period.
What is saltatory conduction?
found in myelinated nerves.
AP only generate at nodes of Ranvier since voltage regulated Na channels only exist at nodes of Ranvier. AP flows between node to next node.
Does not waste time generating APs in membrane covered by myelin, therefore it is fast.
How does myelinated axon compare to that of an unmyelinated axon with the same diamter
myelinated would have a faster conduction velocity.
More on action [potential
- the size and shape of action potentials are not influenced by the size of the stimulus
- What is the duration of an action potential? 1 - 5 msec
-What is overshoot described as in the action potential generation? The point at which the membrane potential becomes positive
What is happening during repolarization? Na+ channels are inactivated and K+ are opened
-the voltage gated K+ channel has a single slow gate whereas voltage gated Na+ channel has both fast and slow gates
- What is the refractory period? The time when it is either impossible or more difficult to generate a second action potential
- What is absolute refractory? The period in which the voltage gated channels have not reset and therefore do not respond to stimulation
- What is relative refractory? This is during the period positive after potential in which the cell is hyperpolarized and is more difficult to generate a second potential
-What is voltage Inactivation? A cell membrane is maintained at a voltage potential above threshold and the voltage gated channels are not reset then action potentials can not be generated
-What is accomodation to slow depoalarization? This is what happens when a slow depolarizaion occurs which does not cause the voltage gated channels to respond and in turn does not produce an action potential
Describe key features of action potentials.
-long distance signal, can travel over many space constants
-spread is nondecremental fashion-stays the same size as spread
-threshold for generation of action potential. Small depolarizations do not reach threshold and dies away, if depolarization reaches threshold generate action potential which can spread down axon.
-it is an all or none principle-size of action potential DOES NOT depend on the size of the triggering stimulus.
What are the various stages of an action potential?
1. Cell rest, polarized-cell negative inside
2. Depolarization phage-sometimes called rising phase-due to opening of sodium channels (activation gate) Na rushes IN maintaining cell less negative
3. Overshoot-variable-where you actual make membrane potential positive, not all cells get this
4. Peak action potential
5. Repolarization phase-sometimes called falling phase-Na channel closes, K channel opens so K rushes OUT of the cell. Before the only thing holding K inside the cell was that it was negative inside bc K is in higher concentration inside the cell. Now that the inside of the cell is positive, there is both an electrical and chemical force pushing it out.
6. Hyperpolarization-sometimes called undershoot phase. K channels remain OPEN long enough, cell gets close to K Nernst potential.
Explain the concept of a threshold.
1. sufficient depolarization to trigger an AP
2. value of membrane potential at which inward flow of Na exceed the passive outward flow of K, so enter positive feedback cycle causing rapid depolarization.
3. Usually lowest at the initial segment of axon so that is where that AP is usually generated in most neurons
4. Initial segment of axon extends from axon hillock about 20 to 50 micrometers down the axon In myelinated axons initial segment and at the first segment of myelin sheath
5. In sensory neurons information is conveyed from peripheral sensory ending to the CNS. APs are first generated in the peripheral axon trigger zone and conducted towards the cell soma.
Do the Na or K concentration gradients change before or after an action potential?
No, they are identical before and after with K being higher inside the cell and Na being higher outside the cell. So few ions are needed to be moved to create an action potential, it does not change the overall concentration of the cell.
Here are questions related to this topic
Q__________Post valentine Action potential=====q1 to 30
Q___________action potential/RMP===============q31 to 41
Let me know if you see mistakes.
