6.6 Membrane Potential & the Action Potential

Resting Membrane Potential

All excitable cells (neurons, muscle, endocrine) maintain an electrical potential difference across the plasma membrane — the resting membrane potential (RMP). In a typical neuron the RMP is approximately -70 mV (inside negative relative to outside). This potential arises from:

1. Concentration gradients of ions established by the Na+/K+-ATPase (high intracellular K+, low intracellular Na+).
2. Selective permeability — at rest, the membrane is far more permeable to K+ than to Na+ because of numerous K+ leak channels.

Nernst Equation

The equilibrium potential for an ion (the membrane voltage at which net flux is zero) is given by the Nernst equation:

E_ion = (RT/zF) · ln([ion]_outside / [ion]_inside)

At 37°C, this simplifies to:

E_ion = (61.5 / z) · log10([ion]_outside / [ion]_inside)

Typical values (mammalian neuron):

The RMP (-70 mV) is closest to E_K (-90 mV) because at rest the membrane is most permeable to K+.

Goldman-Hodgkin-Katz (GHK) Equation

The GHK equation accounts for multiple ion permeabilities (P):

V_m = (RT/F) · ln[(P_K[K+]_o + P_Na[Na+]_o + P_Cl[Cl-]_i) / (P_K[K+]_i + P_Na[Na+]_i + P_Cl[Cl-]_o)]

At rest, P_K >> P_Na, so the RMP approaches E_K. During the action potential upstroke, P_Na rises sharply and Vm approaches E_Na.

Graded Potentials

Graded potentials are local changes in membrane potential produced by ligand-gated or mechanically gated channels. They are:

• Graded in amplitude — larger stimulus produces larger potential.
• Decremental — decay with distance due to leaky membrane.
• Summating — temporal and spatial summation occur at the axon hillock.

Excitatory postsynaptic potentials (EPSPs) depolarize; inhibitory postsynaptic potentials (IPSPs) hyperpolarize. If the summed potential at the axon hillock (initial segment) reaches threshold (~-55 mV), an action potential fires.

The Action Potential

An action potential (AP) is an all-or-none, regenerative, non-decremental depolarization. The classic neuronal AP has the following phases:

1. Threshold — when Vm reaches ~-55 mV, voltage-gated Na+ channels open.
2. Depolarization (upstroke) — rapid Na+ influx drives Vm toward E_Na (~+30 mV peak). Voltage-gated Na+ channels open rapidly.
3. Repolarization — Na+ channels inactivate (a separate ball-and-chain mechanism), and slower voltage-gated K+ channels open, allowing K+ efflux that returns Vm toward E_K.
4. Afterhyperpolarization — K+ channels remain open longer than needed, driving Vm briefly below RMP toward E_K, then close, restoring RMP.

Voltage-Gated Channels

• Voltage-gated Na+ channel — has activation gate (opens on depolarization) and inactivation gate (closes after ~1 ms). Local anesthetics (lidocaine) bind open/inactivated channels preferentially.
• Voltage-gated K+ channel — opens on depolarization but slowly (delayed rectifier), responsible for repolarization.
• Voltage-gated Ca2+ channels — in cardiac and smooth muscle, contribute to plateau phase; in presynaptic terminals, trigger neurotransmitter release.

Refractory Periods

• Absolute refractory period — from AP upstroke through early repolarization, when Na+ channels are inactivated; no stimulus, however strong, can fire another AP. Prevents backward propagation and sets the maximum firing frequency.
• Relative refractory period — during afterhyperpolarization, when some Na+ channels have recovered but the membrane is hyperpolarized; only a stronger-than-normal stimulus can fire an AP.

Propagation of Action Potentials

At the peak of an AP, intracellular Na+ locally depolarizes adjacent membrane, opening neighboring Na+ channels — the AP propagates without losing amplitude. Velocity depends on:

• Axon diameter — larger diameter = lower internal resistance = faster conduction.
• Myelination — Schwann cells (PNS) and oligodendrocytes (CNS) wrap the axon in myelin, leaving gaps called nodes of Ranvier. Current jumps from node to node — saltatory conduction — increasing velocity up to ~120 m/s in large myelinated fibers vs ~1 m/s in small unmyelinated fibers.

Multiple sclerosis destroys CNS myelin, slowing and ultimately blocking conduction. Guillain-Barré syndrome is an analogous PNS demyelinating disease.

Cardiac Action Potential (Specialization)

Cardiac ventricular APs differ from neuronal APs in having a prolonged plateau phase (~200–300 ms) sustained by L-type Ca2+ channels, which allows time for mechanical contraction before repolarization. The long absolute refractory period prevents tetany in cardiac muscle.

Smooth Muscle APs

Smooth muscle APs are slower, with Ca2+ (rather than Na+) carrying much of the depolarizing current, and can have plateau phases (e.g., uterine, vascular smooth muscle).

Clinical Correlations

• Hyperkalemia — high extracellular K+ depolarizes RMP (less negative), inactivating Na+ channels, slowing conduction, and causing peaked T waves, widened QRS, and risk of cardiac arrest.
• Hypokalemia — low extracellular K+ hyperpolarizes RMP, making cells less excitable; causes muscle weakness, U waves on ECG.
• Local anesthetics — block voltage-gated Na+ channels preferentially in rapidly firing fibers (use-dependent block).
• Tetrodotoxin (pufferfish) and saxitoxin — block voltage-gated Na+ channels, causing paralysis.
• Long QT syndrome — mutations in K+ channels (HERG/KCNH2) or Na+ channels delay repolarization, predisposing to torsades de pointes.

Summary of AP Steps

1. Resting potential set by K+ leak and Na+/K+-ATPase.
2. Depolarization to threshold opens voltage-gated Na+ channels.
3. Na+ influx drives upstroke toward +30 mV.
4. Na+ channels inactivate; delayed K+ channels open.
5. K+ efflux repolarizes membrane.
6. Brief afterhyperpolarization; Na+/K+-ATPase restores gradients.
7. Absolute refractory period (Na+ inactivated) → relative refractory period (K+ still elevated).