title: The position of the fast-inactivation gate during lidocaine block of voltage-gated Na+ channels.
abstract: 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 alpha 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.
authors.affiliation: Program in Neuroscience, Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: V
authors.initials: V
authors.lastname: Vedantham
authors.forename: S C
authors.initials: SC
authors.lastname: Cannon
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D004558:Electric Stimulation; D004594:Electrophysiology; D015640:Ion Channel Gating / Q000187:drug effects*; D008012:Lidocaine / Q000494:pharmacology*; D008564:Membrane Potentials / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000096:biosynthesis; D014981:Xenopus
chemical_list: D000779:Anesthetics, Local; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D008012:Lidocaine