Mechanistic link between lidocaine block and inactivation probed by outer pore mutations in the rat μ1 skeletal muscle sodium channel

Nicholas G. Kambouris, Laura A. Hastings, Svetlana Stepanovic, Eduardo Marban, Gordon F. Tomaselli, Jeffrey R. Balser

Research output: Contribution to journalArticle


1. Mutations that disrupt Na+ channel fast inactivation attenuate lidocaine (lignocaine)-induced use dependence; however, the pharmacological role of slower inactivation processes remains unclear. In Xenopus oocytes, tryptophan substitution in the outer pore of the rat skeletal muscle channel (μ1-W402) alters partitioning among fast- and slow-inactivated states. We therefore examined the effects of W402 mutations on lidocaine block. 2. Recovery from inactivation exhibited three kinetic components (I(F), fast; I(M), intermediate; I(S), slow). The effects of W402A and W402S on I(F) and I(S) differed, but both mutants (with or without β1 subunit coexpression) decreased the amplitude of I(M). In wild-type channels, lidocaine imposed a delayed recovery component with intermediate kinetics, and use-dependent block was attenuated in both W402A and W402S. 3. To examine the pharmacological role of I(S) relative to I(M), drug-exposed β1-coexpressed channels were subjected to 2 min depolarizations. Lidocaine had no effect on sodium current (I(Na)) after a 1 s hyperpolarization interval that allowed recovery from I(M) but not I(S), suggesting that lidocaine affinity for I(S) is low. 4. Both W402 mutations reduced occupancy of I(M) in drug-free conditions, and also induced resistance to use-dependent block. We propose that lidocaine-induced use dependence may involve an allosteric conformational change in the outer pore.

Original languageEnglish (US)
Pages (from-to)693-705
Number of pages13
JournalJournal of Physiology
Issue number3
StatePublished - Nov 1 1998


ASJC Scopus subject areas

  • Physiology

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