The position of the fast-inactivation gate during lidocaine block of voltage-gated Na+ channels

Vasanth Vedantham, Stephen C. Cannon

Research output: Contribution to journalArticlepeer-review

98 Scopus citations


Lidocaine produces voltage- and use-dependent inhibition of voltage- gated Na+ channels through preferential binding to channel conformations that are normally populated at depolarized potentials and by slowing the rate of Na+ channel repriming after depolarizations. It has been proposed that the fast-inactivation mechanism plays a crucial role in these processes. However, the precise role of fast inactivation in lidocaine action has been difficult to probe because gating of drug-bound channels does not involve changes in ionic current. For that reason, we employed a conformational marker for the fast-inactivation gate, the reactivity of a cysteine substituted at phenylalanine 1304 in the rat adult skeletal muscle sodium channel α subunit (rSkM1) with [2- (trimethylammonium)ethyl]methanethiosulfonate (MTS-ET), to determine the position of the fast-inactivation gate during lidocaine block. We found that lidocaine does not compete with fast-inactivation. Rather, it favors closure of the fast-inactivation gate in a voltage-dependent manner, causing a hyperpolarizing shift in the voltage dependence of site 1304 accessibility that parallels a shift in the steady state availability curve measured for ionic currents. More significantly, we found that the lidocaine-induced slowing of sodium channel repriming does not result from a slowing of recovery of the fast-inactivation gate, and thus that use-dependent block does not involve an accumulation of fast-inactivated channels. Based on these data, we propose a model in which transitions along the activation pathway, rather than transitions to inactivated states, play a crucial role in the mechanism of lidocaine action.

Original languageEnglish (US)
Pages (from-to)7-16
Number of pages10
JournalJournal of General Physiology
Issue number1
StatePublished - Jan 1999


  • Antiarrhythmic
  • Local anesthetic
  • Methanethiosulfonate
  • Patch clamp
  • SkM1

ASJC Scopus subject areas

  • Physiology


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