The action potential is an all-or-none, regenerative electrical impulse generated across the excitable neuronal plasma membrane, driven by sequential, voltage-dependent changes in sodium and potassium permeabilities.
1. Biophysical Foundations: Resting Potential & Ion Distribution
In resting neurons, an electrical potential difference of approximately -70 mV exists across the plasma membrane (interior negative relative to the extracellular fluid). This resting membrane potential ($V_m$) is maintained by:
- Asymmetric Ionic Distribution: High intracellular potassium ($[K^+]_{in} pprox 140 ext{ mM}$) and low intracellular sodium ($[Na^+]_{in} pprox 14 ext{ mM}$), balanced against extracellular fluid ($[Na^+]_{out} pprox 145 ext{ mM}$, $[K^+]_{out} pprox 4 ext{ mM}$, $[Cl^-]_{out} pprox 110 ext{ mM}$).
- Differential Permeability: At rest, resting leak potassium channels (K2P / inward rectifiers) are substantially more permeable than sodium channels ($P_K : P_{Na} : P_{Cl} pprox 1 : 0.04 : 0.45$).
- Na+/K+ ATPase Pump: Active primary transport expelling 3 $Na^+$ ions in exchange for 2 $K^+$ ions entering per ATP hydrolyzed, electrogenically contributing ~ -3 to -5 mV and maintaining steep concentration gradients.
$$V_m = rac{RT}{F} ln left( rac{P_K [K^+]_{out} + P_{Na} [Na^+]_{out} + P_{Cl} [Cl^-]_{in}}{P_K [K^+]_{in} + P_{Na} [Na^+]_{in} + P_{Cl} [Cl^-]_{out}}
ight)$$
Where $R$ is the universal gas constant, $T$ is absolute temperature, $F$ is Faraday’s constant, and $P_x$ represents the relative membrane permeability of each ion.
Neuronal Action Potential & Voltage-Gated Channel Conductances
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2. The Molecular Mechanism: Voltage-Gated Na+ and K+ Channels
The action potential comprises four tightly synchronized physiological phases:
When membrane potential depolarizes to threshold (~ -55 mV), the S4 voltage sensor domain in Nav1.x channels shifts outwardly, opening the activation m-gate. Inward Na+ current depolarizes the cell regeneratively in a positive feedback loop (Hodgkin cycle).
At +30 to +40 mV, the intracellular IFM (Isoleucine-Phenylalanine-Methionine) inactivation motif swings into the channel pore (h-gate closure), terminating Na+ influx within ~1 ms.
Delayed-rectifier Kv channels (Kv1.x / Kv2.x) open slowly with delayed kinetics. Massive potassium efflux rapidly repolarizes the membrane back toward the K+ equilibrium potential.
Because Kv channels close slowly, membrane potential dips toward E_K (-80 to -90 mV). Absolute refractory period prevents backwards propagation; relative refractory period requires suprathreshold stimulus.
3. Quantitative Comparison: Unmyelinated vs Myelinated Axons
| Conduction Property | Unmyelinated Axon (Continuous) | Myelinated Axon (Saltatory) |
|---|---|---|
| Conduction Velocity | 0.5 โ 2.0 m/s (C-fibers) | Up to 120 m/s (A-alpha fibers) |
| Channel Distribution | Uniformly distributed along membrane (~100โ200 channels/ฮผmยฒ) | Extremely dense at Nodes of Ranvier (~2,000โ12,000 channels/ฮผmยฒ); negligible in internodes |
| Membrane Capacitance ($C_m$) | High (slow charging of membrane) | Extremely low (myelin increases effective dielectric thickness) |
| Membrane Resistance ($R_m$) | Low (current leaks out through channels) | Extremely high across internodes (prevents radial ionic leakage) |
| Metabolic Cost (ATP) | High (Na+/K+ pump required across entire surface) | Low (~1% of unmyelinated; pumping localized only to nodes) |
4. Clinical Neuropharmacology & Channelopathies
- Tetrodotoxin (TTX) & Saxitoxin (STX): Potent heterocyclic guanidinium neurotoxins from pufferfish and dinoflagellates that physically occlude the extracellular pore vestibule of voltage-gated Na+ channels, causing rapid neuromuscular paralysis.
- Local Anesthetics (Lidocaine, Bupivacaine): Hydrophobic tertiary amines that traverse the membrane and bind stereospecifically to the inner S6 segment of Nav channels in their inactivated state, blocking conduction (use-dependent block).
- Multiple Sclerosis (MS): Autoimmune inflammatory demyelination of CNS oligodendrocytes. Loss of internodal resistance exposes unmyelinated membrane devoid of adequate Na+ channels, causing conduction block and neurological deficits.
Answer: Moderate persistent depolarization shifts resting potential closer to threshold, but chronically inactivates voltage-gated sodium channels (h-gate closure), leaving fewer functional channels available to trigger action potentials (depolarization block).