Voltage-gated sodium channels (Nav1.x)

Category: membrane

Overview

Nav1.x voltage-gated Na+ channels generate the action-potential upstroke. Pharmacology blocks the channel in its open or inactivated state, preferentially silencing rapidly-firing neurons (use-dependent block). Anticonvulsants (phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, lacosamide, zonisamide) raise the seizure threshold by slowing recovery from inactivation. Local anesthetics (lidocaine, bupivacaine, ropivacaine, articaine, mepivacaine) achieve regional sensory block by depolarization-induced channel binding from inside the membrane; cardiotoxicity is dose-dependent (bupivacaine highest — racemic mix risk, levobupivacaine + ropivacaine were developed to reduce CV risk). Topical surface anesthetics (benzocaine, pramoxine) have the same fundamental MOA but stay extracellular. Methemoglobinemia is a benzocaine + prilocaine specific risk.

Organ Systems

Pathway Steps

  1. membrane-depolarization → na-channel-opening — via Nav1.x activation → AP upstroke. Voltage-gated sodium channels open within microseconds of membrane depolarization, allowing the Na⁺ influx that drives the rising phase of the action potential. This regenerative depolarization is the basis of electrical signaling in neurons and muscle — and the target of local anesthetics and class-I antiarrhythmics.
  2. na-channel-opening → na-channel-inactivation — via fast inactivation (h-gate) closes the channel within 1 ms — anticonvulsants stabilize this state. Within milliseconds the channel inactivates (a hinged intracellular gate occludes the pore), ending the Na⁺ current and setting the refractory period. Many anticonvulsants (phenytoin, carbamazepine, lamotrigine) preferentially stabilize this inactivated state in rapidly firing neurons — a use-dependent block.

Known Modulators

References