Neurology
Action Potential
How a neuron fires — voltage-gated sodium and potassium channels in 2 milliseconds
An action potential is the all-or-none electrical spike that neurons, cardiac myocytes, and skeletal muscle use to communicate. It begins when membrane depolarization crosses threshold (~−55 mV in neurons), opens voltage-gated sodium channels, and drives the membrane toward +30 mV in under a millisecond. Sodium channels then inactivate, voltage-gated potassium channels open, and the membrane repolarizes — overshooting briefly into hyperpolarization before the Na⁺/K⁺-ATPase restores the resting gradient. The whole event takes 1-2 ms in axons and propagates without decrement.
- Resting potential−70 mV (neurons), −90 mV (cardiac)
- Threshold~−55 mV
- Peak depolarization+30 to +40 mV
- Duration1-2 ms (neurons), 200-300 ms (cardiac)
- Conduction velocity0.5-120 m/s (myelin-dependent)
- Refractory periodAbsolute then relative
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Why action potentials matter
- Anesthesia. Local and regional blocks rely entirely on shutting down voltage-gated sodium channels in nociceptive fibers.
- Cardiology. Antiarrhythmic classes I-IV are organized by which ion channel they target during the cardiac action potential.
- Neurology. Multiple sclerosis, Guillain-Barré, and demyelinating neuropathies are diseases of conduction velocity.
- Epilepsy. Seizures are pathological, synchronized hyperexcitation; first-line drugs stabilize sodium channels.
- Toxicology. Tetrodotoxin from pufferfish and saxitoxin from shellfish block sodium channels and cause flaccid paralysis.
- Critical care. Hyperkalemia depolarizes the resting membrane toward threshold, eventually inactivating sodium channels and arresting the heart.
- Pain medicine. Nav1.7 and Nav1.8 inhibitors are an active drug-development frontier for non-opioid analgesia.
Common misconceptions
- "Bigger stimulus = bigger action potential." Action potentials are all-or-none; stimulus intensity is encoded by firing rate, not amplitude.
- "The Na⁺/K⁺ pump drives the spike." The pump only sets up gradients; the spike itself is passive ion flow through gated channels.
- "Myelin conducts the signal." Myelin is an insulator; it forces current to leap between unmyelinated nodes.
- "Hyperkalemia depolarizes, so it must increase excitability." Sustained depolarization inactivates sodium channels — the heart slows and arrests.
- "Refractory means tired." It is a structural state of inactivated channels, not energetic depletion.
- "Local anesthetics block all nerves equally." Small unmyelinated C fibers are blocked first; large motor fibers last — pain leaves before strength.
Frequently asked questions
What sets the resting membrane potential?
Mainly the K⁺ leak channels and the Na⁺/K⁺-ATPase. The pump uses ATP to push 3 Na⁺ out and 2 K⁺ in, building chemical gradients. Because the resting membrane is much more permeable to K⁺ than Na⁺, the potential sits near the potassium equilibrium potential of about −90 mV, modified by some Na⁺ leak to give −70 mV in typical neurons. Disruption of ATP supply collapses this gradient within minutes — the basis of ischemic neuronal injury.
How does depolarization propagate?
Local current from an active patch flows passively to neighboring membrane, depolarizing it to threshold. Once threshold is crossed, the next segment fires, regenerating the spike. In unmyelinated axons this happens continuously and slowly. In myelinated axons, the spike jumps from one node of Ranvier to the next — saltatory conduction — boosting velocity 50-fold. Myelin loss in multiple sclerosis slows or blocks conduction.
What is the refractory period?
After a spike, sodium channels are inactivated and cannot open regardless of stimulus — the absolute refractory period (~1 ms). They recover only when the membrane repolarizes. The relative refractory period follows, when potassium channels are still open and a stronger-than-usual stimulus is needed. The refractory period sets the maximum firing rate (~500 Hz in fast neurons) and ensures unidirectional propagation along the axon.
How do local anesthetics work?
Lidocaine, bupivacaine, and similar drugs are weak bases that cross the membrane in their uncharged form, then ionize and bind voltage-gated sodium channels from the cytoplasmic side. They preferentially block channels in the open or inactivated state — use-dependent block — so rapidly firing nociceptive fibers are silenced first. Adding epinephrine prolongs the block by reducing local blood flow and washout.
Why does cardiac action potential look different?
Cardiac ventricular myocytes have a long plateau phase from L-type calcium channels balancing potassium efflux, lasting 200-300 ms. This plateau triggers contraction via calcium-induced calcium release and prevents tetanic contraction by enforcing a long refractory period. Many antiarrhythmics (sotalol, amiodarone, dofetilide) work by prolonging this plateau; QT prolongation is the side effect of concern.
What if sodium channels are dysfunctional?
Loss-of-function Nav1.7 mutations cause congenital insensitivity to pain — patients cannot feel injuries. Gain-of-function mutations in the same channel cause erythromelalgia, a syndrome of burning extremity pain. Cardiac SCN5A mutations cause Brugada syndrome and long QT type 3. Many epilepsies trace to sodium channel variants, which is why phenytoin, carbamazepine, and lamotrigine all act on these channels.
How is calcium involved?
At the axon terminal, depolarization opens voltage-gated calcium channels. The Ca²⁺ influx triggers vesicle fusion and neurotransmitter release within ~200 microseconds. This is the link between electrical signaling in the axon and chemical signaling at the synapse. Calcium-channel blockers, magnesium, and botulinum toxin all interfere here, with effects ranging from blood pressure control to muscle paralysis.