Lidocaine induces a slow inactivated state in rat skeletal muscle sodium channels

被引:56
作者
Chen, ZH
Ong, BH
Kamouris, NG
Marbán, E
Tomaselli, GF
Balser, JR
机构
[1] Vanderbilt Univ, Sch Med, Dept Anesthesiol, Nashville, TN 37212 USA
[2] Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37212 USA
[3] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA
[4] Johns Hopkins Univ, Sch Med, Inst Mol Cardiobiol, Baltimore, MD 21205 USA
来源
JOURNAL OF PHYSIOLOGY-LONDON | 2000年 / 524卷 / 01期
关键词
D O I
10.1111/j.1469-7793.2000.t01-1-00037.x
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 (mu l) 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).
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页码:37 / 49
页数:13
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