Mechanism for the effects of extracellular acidification on HERG-channel function

被引:39
作者
Jiang, M [1 ]
Dun, W [1 ]
Tseng, GN [1 ]
机构
[1] Columbia Univ, Dept Pharmacol, New York, NY 10032 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY | 1999年 / 277卷 / 04期
关键词
rapid delayed rectifier channel; C-type inactivation; deactivation; mutagenesis;
D O I
10.1152/ajpheart.1999.277.4.H1283
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Human ether-a-go-go-related gene (HERG) encodes a K channel similar to the rapid delayed rectifier channel current (I-Kr) in cardiac myocytes. Modulation of I-Kr by extracellular acidosis under pathological conditions may impact on cardiac electrical activity. Therefore, we studied the effects of extracellular acidification on I-Kr function and the underlying mechanism, using HERG expressed in Xenopus oocytes as a model. Acidification [extracellular pH (pH(o)) 8.5-6.5] accelerated HERG deactivation (at -80 mV, the time constant tau of the major component of deactivation was 253 +/- 17, 158 +/- 10, and 65 +/- 5 ms at pH(o) 8.5, 7.5, and 6.5, respectively; n = 7-10 each), with no effects on other gating kinetics except a modest acceleration of recovery from inactivation (at -80 mV, tau of recovery was 4.7 +/- 0.3, 3.8 +/- 0.3, and 1.3 +/- 0.2 ms at pH(o) 8.5, 7.5, and 6.5, respectively; n = 4-7 each). The following were ruled out as the underlying mechanisms: 1) voltage shift in channel activation, 2) pore blockade by protons, 3) protonation of histidines on the extracellular domain of HERO, 4) acceleration of recovery from C-type inactivation, and 5) interaction between an external H+ binding site and the cytoplasmic NH2-terminal domain (a key determinant of HERG deactivation rate). Extracellular application of diethylpyrocarbonate caused an irreversible acceleration of HERO deactivation and prevented further acceleration by external acidification. Our data suggest that side chains accessible to the extracellular solution mediated the effects of elevating extracellular H+ concentration on channel deactivation.
引用
收藏
页码:H1283 / H1292
页数:10
相关论文
共 33 条
[1]   Structural implications of fluorescence quenching in the Shaker K+ channel [J].
Cha, A ;
Bezanilla, F .
JOURNAL OF GENERAL PHYSIOLOGY, 1998, 112 (04) :391-408
[2]   IDENTIFICATION AND MOLECULAR LOCALIZATION OF A PH-SENSING DOMAIN FOR THE INWARD RECTIFIER POTASSIUM CHANNEL HIR [J].
COULTER, KL ;
PERIER, F ;
RADEKE, CM ;
VANDENBERG, CA .
NEURON, 1995, 15 (05) :1157-1168
[3]   Ionic mechanisms of regional action potential heterogeneity in the canine right atrium [J].
Feng, JL ;
Yue, LX ;
Wang, ZG ;
Nattel, S .
CIRCULATION RESEARCH, 1998, 83 (05) :541-551
[4]   SLOWING OF SODIUM-CHANNEL OPENING KINETICS IN SQUID AXON BY EXTRACELLULAR ZINC [J].
GILLY, WF ;
ARMSTRONG, CM .
JOURNAL OF GENERAL PHYSIOLOGY, 1982, 79 (06) :935-964
[5]   Two components of delayed rectifier current in canine atrium and ventricle - Does I-Ks play a role in the reverse rate dependence of class III agents? [J].
Gintant, GA .
CIRCULATION RESEARCH, 1996, 78 (01) :26-37
[6]   Time course and voltage dependence of expressed HERG current compared with native "rapid" delayed rectifier K current during the cardiac ventricular action potential [J].
Hancox, JC ;
Levi, AJ ;
Witchel, HJ .
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, 1998, 436 (06) :843-853
[7]  
Hille B., 1992, IONIC CHANNELS EXCIT, P445
[8]   The activation gate of a voltage-gated K+ channel can be trapped in the open state by an intersubunit metal bridge [J].
Holmgren, M ;
Shin, KS ;
Yellen, G .
NEURON, 1998, 21 (03) :617-621
[9]   ELECTROPHYSIOLOGICAL MECHANISMS OF VENTRICULAR ARRHYTHMIAS RESULTING FROM MYOCARDIAL ISCHEMIA AND INFARCTION [J].
JANSE, MJ ;
WIT, AL .
PHYSIOLOGICAL REVIEWS, 1989, 69 (04) :1049-1169
[10]  
Jo SH, 1999, BIOPHYS J, V76, pA86