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

被引:55
作者
Kambouris, NG
Hastings, LA
Stepanovic, S
Marban, E
Tomaselli, GF
Balser, JR
机构
[1] Johns Hopkins Univ, Sch Med, Dept Anesthesia & Crit Care Med, Div Cardiac Anesthesiol, Baltimore, MD 21287 USA
[2] Johns Hopkins Univ, Sch Med, Dept Med, Sect Mol & Cellular Cardiol, Baltimore, MD 21287 USA
来源
JOURNAL OF PHYSIOLOGY-LONDON | 1998年 / 512卷 / 03期
关键词
D O I
10.1111/j.1469-7793.1998.693bd.x
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 mu 1-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 beta(1) 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 beta(1)-coexpressed channels were subjected to 2 min depolarizations. Lidocaine had no effect on sodium current (I-Na) after a 1s 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.
引用
收藏
页码:693 / 705
页数:13
相关论文
共 44 条
[1]   EFFECTS OF EXTERNAL POTASSIUM AND LONG DURATION VOLTAGE CONDITIONING ON AMPLITUDE OF SODIUM CURRENTS IN GIANT AXON OF SQUID, LOLIGO P5ALEI [J].
ADELMAN, WJ ;
PALTI, Y .
JOURNAL OF GENERAL PHYSIOLOGY, 1969, 54 (05) :589-&
[2]   IS THERE A 2ND EXTERNAL LIDOCAINE BINDING-SITE ON MAMMALIAN CARDIAC-CELLS [J].
ALPERT, LA ;
FOZZARD, HA ;
HANCK, DA ;
MAKIELSKI, JC .
AMERICAN JOURNAL OF PHYSIOLOGY, 1989, 257 (01) :H79-H84
[3]   Functional consequences of lidocaine binding to slow-inactivated sodium channels [J].
Balser, JR ;
Nuss, HB ;
Romashko, DN ;
Marban, E ;
Tomaselli, GF .
JOURNAL OF GENERAL PHYSIOLOGY, 1996, 107 (05) :643-658
[4]   External pore residue mediates slow inactivation in mu 1 rat skeletal muscle sodium channels [J].
Balser, JR ;
Nuss, HB ;
Chiamvimonvat, N ;
PerezGarcia, MT ;
Marban, E ;
Tomaselli, GF .
JOURNAL OF PHYSIOLOGY-LONDON, 1996, 494 (02) :431-442
[5]   Local anesthetics as effectors of allosteric gating - Lidocaine effects on inactivation-deficient rat skeletal muscle Na channels [J].
Balser, JR ;
Nuss, HB ;
Orias, DW ;
Johns, DC ;
Marban, E ;
Tomaselli, GF ;
Lawrence, JH .
JOURNAL OF CLINICAL INVESTIGATION, 1996, 98 (12) :2874-2886
[6]   Use-dependent blockers and exit rate of the last ion from the multi-ion pore of a K+ channel [J].
Baukrowitz, T ;
Yellen, G .
SCIENCE, 1996, 271 (5249) :653-656
[7]   LIDOCAINE BLOCK OF CARDIAC SODIUM-CHANNELS [J].
BEAN, BP ;
COHEN, CJ ;
TSIEN, RW .
JOURNAL OF GENERAL PHYSIOLOGY, 1983, 81 (05) :613-642
[8]   A MOLECULAR-BASIS FOR GATING MODE TRANSITIONS IN HUMAN SKELETAL-MUSCLE NA+ CHANNELS [J].
BENNETT, PB ;
MAKITA, N ;
GEORGE, AL .
FEBS LETTERS, 1993, 326 (1-3) :21-24
[9]   ON THE MOLECULAR NATURE OF THE LIDOCAINE RECEPTOR OF CARDIAC NA+ CHANNELS - MODIFICATION OF BLOCK BY ALTERATIONS IN THE ALPHA-SUBUNIT III-IV INTERDOMAIN [J].
BENNETT, PB ;
VALENZUELA, C ;
CHEN, LQ ;
KALLEN, RG .
CIRCULATION RESEARCH, 1995, 77 (03) :584-592
[10]   MOLECULAR MECHANISM FOR AN INHERITED CARDIAC-ARRHYTHMIA [J].
BENNETT, PB ;
YAZAWA, K ;
MAKITA, N ;
GEORGE, AL .
NATURE, 1995, 376 (6542) :683-685