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Lidocaine induces a slow inactivated state in rat skeletal muscle sodium channels
Author(s) -
Chen Zhenhui,
Ong¹ BoonHooi,
Kambouris Nicholas G.,
Marbán Eduardo,
Tomaselli Gordon F.,
Balser Jeffrey R.
Publication year - 2000
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1111/j.1469-7793.2000.t01-1-00037.x
Subject(s) - sodium channel , lidocaine , biophysics , chemistry , allosteric regulation , depolarization , sodium , sodium channel blocker , mutagenesis , ion channel , mutant , receptor , biochemistry , biology , neuroscience , organic chemistry , gene
1 Local anaesthetics such as lidocaine (lignocaine) interact with sodium channels in a manner that is exquisitely sensitive to the voltage‐dependent conformational state of the ion channel. When depolarized in the presence of lidocaine, sodium channels assume a long‐lived quiescent state. Although studies over the last decade have localized the lidocaine receptor to the inner aspect of the aqueous pore, the mechanistic basis of depolarization‐induced ‘use‐dependent’ lidocaine block remains uncertain. 2 Recent studies have shown that lowering the extracellular Na + concentration ([Na + ] o ) and mutations in the sodium channel outer P‐loop modulate occupancy of a quiescent ‘slow’ inactivated state with intermediate kinetics (termed I M ) that involves structural rearrangements in the outer pore. 3 Site‐directed mutagenesis and ion‐replacement experiments were performed using voltage‐clamped Xenopus oocytes and cultured (HEK‐293) cells expressing wild‐type and mutant rat skeletal muscle (μ1) sodium channels. 4 Our results show that lowering [Na + ] o potentiates use‐dependent lidocaine block. The effect of [Na + ] o is maintained despite a III‐IV linker mutation that partially disrupts fast inactivation (F1304Q). In contrast, the effect of lowering [Na + ] o on lidocaine block is reduced by a P‐loop mutation (W402A) that limits occupancy of I M . 5 Our findings are consistent with a simple allosteric model where lidocaine binding induces channels to occupy a native slow inactivated state that is inhibited by [Na + ] o .