Compound-specific Na+ channel pore conformational changes induced by local anaesthetics

被引:21
作者
Fukuda, K
Nakajima, T
Viswanathan, PC
Balser, JR
机构
[1] Vanderbilt Univ, Sch Med, Dept Anaesthesiol, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37232 USA
来源
JOURNAL OF PHYSIOLOGY-LONDON | 2005年 / 564卷 / 01期
关键词
D O I
10.1113/jphysiol.2004.081646
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Upon prolonged depolarizations, voltage-dependent Na+ channels open and subsequently inactivate, occupying fast and slow inactivated conformational states. Like C-type inactivation in K+ channels, slow inactivation is thought to be accompanied by rearrangement of the channel pore. Cysteine-labelling studies have shown that lidocaine, a local anaesthetic (LA) that elicits depolarization-dependent ('use-dependent') Na+ channel block, does not slow recovery from fast inactivation, but modulates the kinetics of slow inactivated states. While these observations suggest LA-induced stabilization of slow inactivation could be partly responsible for use dependence, a more stringent test would require that slow inactivation gating track the distinct use-dependent kinetic properties of diverse LA compounds, such as lidocaine and bupivacaine. For this purpose, we assayed the slow inactivation-dependent accessibility of cysteines engineered into domain III, P-segment (mu 1: F1236C, K1237C) to sulfhydryl (MTSEA) modification using a high-speed solution exchange system. As expected, we found that bupivacaine, like lidocaine, protected cysteine residues from MTSEA modification in a depolarization-dependent manner. However, under pulse-train conditions where bupivacaine block of Na+ channels was extensive (due to ultra-slow recovery), but lidocaine block of Na+ channels was not, P-segment cysteines were protected from MTSEA modification. Here we show that conformational changes associated with slow inactivation track the vastly different rates of recovery from use-dependent block for bupivacaine and lidocaine. Our findings suggest that LA compounds may produce their kinetically distinct voltage-dependent behaviour by modulating slow inactivation gating to varying degrees.
引用
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页码:21 / 31
页数:11
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