MEMBRANE ACTION POTENTIAL

FAiq Group

Introduction

• Nerve cells respond to electrical, chemical, or mechanical stimuli
• Neurons communicate via electrical and chemical signaling
• Informations - integrated and transmitted via a single neuron electrically and transmitted to a target cell chemically
• This initiates an electrical change in the target cell
• Electrical signals that depend on the passive properties of the neuronal cell membrane spread electronically over short distances
• These potentials are initiated by local current flow and decay with distance from their site of initiation
• Alternatively, an action potential is an electrical signal that propagates over a long distance without a change in�amplitude

Channels Allow Ions to Flow Through�the Nerve Cell Membrane

• Electrical signals are generated via flow of ions
• Ions can flow across the nerve cell membrane through three types of ion channels: non-gated (leakage), ligand-gated, and voltage-gated
• Non-gated ion channels remain open-responsible for Na+ influx and K+ efflux when the neuron is in its resting state
• Important for the establishment of the RMP (resting membrane potential) & found throughout the neuron
• Ligand-gated ion channels-directly or indirectly activated by chemical neurotransmitters binding to membrane receptors

• Located at sites of synaptic contact & found majorly on dendritic spines, dendrites, and somata
• Voltage-gated ion channels - sensitive to the voltage difference across the membrane; typically closed & open when a critical voltage level is reached
• Found predominantly on axons and axon terminals
• Influx of ion leads to two types of signals:
• - Local, non-propagated potentials called, depending on their location, synaptic, generator, or electrotonic potentials; &
• - Propagated potentials, the action potentials (or nerve impulses)
• The electrical events in neurons are rapid, being measured in milliseconds (ms); and the potential changes are small, being measured in millivolts (mV)�

Resting Membrane Potential (RMP)

• All cells under resting conditions have a potential difference across their plasma membranes with the interior of the cell negatively charged with respect to the outside; this potential is the RMP
• By convention, ECL fluid is assigned a voltage of zero, and the polarity (positive or negative) of the membrane potential is stated in terms of the sign of the excess charge on the inside of the cell
• For example, if the ICL fluid has an excess of negative charge and the potential difference across the�membrane has a magnitude of 90 mV, we say that the�membrane potential is -90 mV
• RMP is measured by voltage clamp technique

• In the unstimulated state, large nerve fibers exhibit a RMP that is approx. -90 mV relative to the ECL fluid
• The RMP reflects a steady state that can be described by the Goldman equation
• This Eq. is derived from diffusion potentials of ions that depends on 3 factors:
• -(1) the polarity of the electrical charge of each ion,
• -(2) the permeability of the membrane (P) to each ion, &
• -(3) the concentrations (C) of the respective ions on the inside (i) and outside (o) of the membrane

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Basic Physics of RMP

• K+ conc. is great inside a nerve fiber membrane but very low outside
• Assume that the membrane is permeable only to the K+ ions
• Due to large K+ conc. gradient from inside toward outside, K+ diffuse outward through the membrane, thus, creating electropositivity outside and electronegativity inside
• Within a mS or so, the potential difference, the diffusion potential, across the membrane becomes great enough to block further net K+ diffusion to the exterior, despite the high K+ conc. gradient

• In the normal mammalian nerve fiber, the potential difference for K+ required is about -94 mV
• Now consider for Na+ with high conc. of Na+ outside the membrane and low Na+ inside
• Assume membrane is permeable to Na+ only
• Diffusion of Na+ to the inside creates a membrane potential of opposite polarity with negativity outside and positivity inside
• Again, the membrane potential rises high enough within mS to block further net diffusion of Na+
• However, this time, in the mammalian nerve fiber, the potential is about 61 millivolts positive inside the fiber

• The diffusion potential level across a membrane that exactly opposes the net diffusion of a particular ion through the membrane is called the Nernst potential for that ion
• The magnitude of Nernst potential is determined by�the ratio of the conc. of that specific ion on the two sides of the membrane
• The greater this ratio, the greater the tendency for the ion to diffuse in one direction, and therefore the greater the Nernst potential required to prevent additional net diffusion
• Nernst potential for any univalent ion can be calculated from the Nernst Eq. at normal body temp. of 98.6°F (37°C) & later used to calculate Goldman Eq. for RMP:

• The diffusion potentials alone caused by K+ and Na+ diffusion would give a membrane potential (MP) of about −86 millivolts, almost all of this being determined by K+ diffusion
• An additional −4 millivolts is contributed to the membrane potential by the continuously acting electrogenic Na⁺-K⁺ pump, giving a net RMP of −90 mV

Nerve Action Potential

• Nerve signals are transmitted by action potentials (Aps) along the nerve fiber membrane
• Each AP begins with a sudden change in the normal�RMP from negative to positive and then ends with an almost equally rapid change back to the negative
• To conduct a nerve signal, the AP moves along the nerve fiber until it comes to the fiber’s end
• The successive stages of the action potential are as�follows:
• Resting Stage: This is the RMP before the AP begins
• The membrane is said to be “polarized” during this stage as −90 mV membrane potential is present

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• Depolarization Stage: In response to a depolarizing stimulus, some of the voltage-gated Na+ channels open and Na+ enters the cell and the MP is brought to its threshold potential (−65 mV)
• The entry of Na+ causes the opening of more voltage-gated Na+ channels and more entry of Na+ inside setting up a positive feedback loop
• The normal “polarized” state of −90 mV is immediately neutralized by the influx of Na+, with the potential rising rapidly in the positive direction; this is called depolarization
• In large nerve fibers, the Na+ entry to the inside cell causes the MP to actually “overshoot” beyond the zero level in positive direction; in some smaller fibers, as well as in many CNS neurons, the potential merely approaches the zero level and does not overshoot to the positive state

• Repolarization Stage: The Na+ channels rapidly�enter a closed state called the inactivated state and remain in this state for a few mS before returning to the resting state, when they again can be activated; also the voltage-gated K+ channels open
• Rapid diffusion of K+ to the exterior re-establishes�the normal negative RMP; this is called repolarization of the membrane
• This lead to full recovery of the RMP within another few mS
• K+ channel remain open for the entire duration of the positive MP and do not close again until after the MP is decreased back to a negative value
• The slow return of the K+ channels to the closed state lead to the after-hyperpolarization followed by a return to the RMP

• ↓ the external Na+ conc. reduces the size of the AP but has little effect on the RMP as the permeability of the membrane to Na+ at rest is relatively low
• Since the RMP is close to the equilibrium potential for K+, changes in the external conc. of this ion can have major effects on the RMP
• If the ECL level of K+ is ↑(hyperkalemia), the RMP moves closer to the threshold for eliciting an AP; thus, the neuron becomes more excitable
• If the ECL level of K+ is ↓ (hypokalemia), the MP is reduced and the neuron is hyperpolarized
• Furthermore, Na+ channels in nerve fibers become the targets of local anesthetic drugs

Role of Ca2+ during the Action Potential

• Ca²⁺ conc. is more than 10,000 times greater in the ECL than the ICL fluid; so great tendency for influx
• Voltage-gated Ca²⁺ channels, slightly permeable to Na⁺ ions and Ca²⁺ ions, have about 1000-fold greater permeability to Ca²⁺ than to Na⁺
• A major function of these channels is to contribute to the depolarizing phase on the AP in some cells
• They are slow channels requiring more times for activation as for the Na⁺ channels (fast channels)
• The conc. of Ca²⁺ in the ECL fluid also has a profound effect on the voltage level at which the Na⁺ channels become activated
• A ↓ in ECL Ca2+ conc. causes Na⁺ channels to be activated (opened) by a small ↑of the MP from its RMP leading to high nerve & muscle excitability

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• Spontaneous discharge occurs in some peripheral nerves, often causing muscle “tetany,” if Ca²⁺ conc. fall only 50 % below normal
• Conversely, an increase in ECL Ca2+ conc. can stabilize the membrane by decreasing excitability
• Ca²⁺ probably appears to bind to the exterior surfaces of the Na⁺ channel protein molecule; the positive charge of Ca²⁺ , in turn, alter the electrical state of the proteins, thus, altering the voltage level required to open the sodium gate
• Alterations in voltage-gated Na⁺ , K⁺ , Ca²⁺ & Cl^- channels, are now known to be the basis of several diseases of nerve and muscle, collectively known as channelopathies

Propagation of the Action Potential

• An AP elicited at any one point on an excitable membrane usually excites adjacent portions of the membrane via Na⁺ influxes, resulting in its propagation
• These Na⁺ influxes represent “local circuits” of current flow from the depolarized areas of the membrane to the adjacent resting membrane areas on both sides
• These inward currents increase the voltage for a distance of 1 to 3 millimeters inside the fiber
• These newly depolarized areas produce still more local circuits of current flow farther along the membrane, causing progressively more and more depolarization
• Thus, the depolarization process travels along the entire length of the fiber; this transmission of the depolarization process along a nerve or muscle fiber is called a nerve or muscle impulse

• The speed with which the AP is propagated along an axon depend on whether the axon is myelinated
• The diameter of the axon also influences the speed of AP conduction: larger-diameter axons have faster AP conduction velocities than smaller-diameter axons����

All-or-Nothing Principle

• If a stimulus of threshold intensity is applied to the nerve fiber, the AP is generated which travels over the entire membrane
• The threshold intensity varies with the duration; with weak stimuli it is long, and with strong stimuli it is short
• The relation between the strength and the duration of a threshold stimulus is called the strength–duration curve
• Increases in the intensity of a stimulus produce no increment or other change in the AP as long as the other experimental conditions remain constant
• The AP fails to occur if the stimulus is subthreshold in magnitude, This is called the all-or-nothing principle, and it applies to all normal excitable tissues

Refractory Period

• An excitable fiber, in which membrane is still depolarized from previous AP, can’t respond to a preceding or newer AP
• The reason is that Na⁺/or Ca²⁺ channels or both present in inactivated state and no excitatory signal of any magnitude can open these inactive channels
• The only condition that will allow channels to reopen & excite the cell next time is for the MP to return to or near the original RMP level
• The period during which a second AP cannot be elicited, even with a strong stimulus, is called the absolute refractory period

• This period for large myelinated nerve fibers is about 1/2500 second
• This indicates that such a fiber can transmit a maximum of about 2500 impulses per second
• However, when repolarization is about one-third complete, the cell can be excited again by a preceding AP of greater magnitude than normal one
• This period lasting from this point to the start of after-depolarization is called relative refractory period

Conduction in Mylinated Neurons

• Myelin is an effective insulator; so in mylinated neurones, the AP proceed on through the axonal membrane via nodes of Ranvier
• Here, depolarization in myelinated axons travels from one node of Ranvier to the next, with the AP at the active node serving to electrotonically depolarize the node ahead of the AP to the firing level
• This “jumping” of depolarization from node to node is called saltatory conduction
• It is a rapid process that allows myelinated axons to conduct up to 50 times faster than the fastest�unmyelinated fibers

Orthodromic & Antidromic Conduction

• An axon can conduct in either direction
• When an AP is initiated in the middle of the axon, two impulses traveling in opposite directions are set up by electrotonic depolarization on either side of the initial AP (current sink)
• In the natural situation, impulses pass in one direction only, ie, from synaptic junctions or receptors along axons to their termination; such conduction is called orthodromic
• Conduction in the opposite direction is called antidromic
• An antidromic impulse will fail to pass the first synapse they encounter and die out at that point