Allosteric effects of mutations in the extracellular S5-P loop on the grating and ion permeation properties of the hERG potassium channel

被引:38
作者
Dun, W [1 ]
Jiang, M [1 ]
Tseng, GN [1 ]
机构
[1] Virginia Commonwealth Univ, Med Coll Virginia, Dept Physiol, Richmond, VA 23298 USA
来源
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY | 1999年 / 439卷 / 1-2期
关键词
activation gating; C-type inactivation; I-Kr; ion selectivity; LQT2; structure-function relation;
D O I
10.1007/s004240051138
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
The hERG channel has an unusually long (39 amino acids) extracellular loop between the transmembrane S5 segment and the pore region that may play a role in channel function. We explored this possibility by mutating two histidine residues in this region (H578 and H587, referred to as H-1 and H-2) to various residues and examined the resulting changes in channel function. Both positions. could tolerate drastic changes in sidechain properties (proline, cysteine, glutamate and lysine), indicating that they are solvent exposed. None of the H-1 mutations affected hERG channel function. On the other hand, although replacing H-2 with glutamate had little or no effect on hERG properties, putting a proline or lysine at this position disrupted the C-type inactivation process and the pore's K selectivity. There was also a hyperpolarizing shift in the voltage dependence of activation. The phenotype of the H2C mutant was similar to that of H2P or H2K. However, dithiothreitol (DTT, a thiol-reducing agent) treatment converted the H2C phenotype to that of the wild-type channel. These observations suggest:that the peptide backbone conformation around position 587 in the extracellular S5-P loop of hERG channel can affect the channel's gating and ion selectivity functions.
引用
收藏
页码:141 / 149
页数:9
相关论文
共 26 条
[1]   Missense mutation in the pore region of HERG causes familial long QT syndrome [J].
Benson, DW ;
MacRae, CA ;
Vesely, MR ;
Walsh, EP ;
Seidman, JG ;
Seidman, CE ;
Satler, CA .
CIRCULATION, 1996, 93 (10) :1791-1795
[2]   DETERMINATION OF IONIC PERMEABILITY COEFFICIENTS OF THE PLASMA-MEMBRANE OF XENOPUS-LAEVIS OOCYTES UNDER VOLTAGE CLAMP [J].
COSTA, PF ;
EMILIO, MG ;
FERNANDES, PL ;
FERREIRA, HG ;
FERREIRA, KG .
JOURNAL OF PHYSIOLOGY-LONDON, 1989, 413 :199-211
[3]   A MOLECULAR-BASIS FOR CARDIAC-ARRHYTHMIA - HERG MUTATIONS CAUSE LONG QT SYNDROME [J].
CURRAN, ME ;
SPLAWSKI, I ;
TIMOTHY, KW ;
VINCENT, GM ;
GREEN, ED ;
KEATING, MT .
CELL, 1995, 80 (05) :795-803
[4]   The structure of the potassium channel:: Molecular basis of K+ conduction and selectivity [J].
Doyle, DA ;
Cabral, JM ;
Pfuetzner, RA ;
Kuo, AL ;
Gulbis, JM ;
Cohen, SL ;
Chait, BT ;
MacKinnon, R .
SCIENCE, 1998, 280 (5360) :69-77
[5]   Effects of outer mouth mutations on hERG channel function:: A comparison with similar mutations in the Shaker channel [J].
Fan, JS ;
Jiang, M ;
Dun, W ;
McDonald, TV ;
Tseng, GN .
BIOPHYSICAL JOURNAL, 1999, 76 (06) :3128-3140
[6]   MUTATIONS IN THE K+ CHANNEL SIGNATURE SEQUENCE [J].
HEGINBOTHAM, L ;
LU, Z ;
ABRAMSON, T ;
MACKINNON, R .
BIOPHYSICAL JOURNAL, 1994, 66 (04) :1061-1067
[7]   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
[8]   Mechanism for the effects of extracellular acidification on HERG-channel function [J].
Jiang, M ;
Dun, W ;
Tseng, GN .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 1999, 277 (04) :H1283-H1292
[9]   Contribution of the selectivity filter to inactivation in potassium channels [J].
Kiss, L ;
LoTurco, J ;
Korn, SJ .
BIOPHYSICAL JOURNAL, 1999, 76 (01) :253-263
[10]   Transmembrane movement of the Shaker K+ channel S4 [J].
Larsson, HP ;
Baker, OS ;
Dhillon, DS ;
Isacoff, EY .
NEURON, 1996, 16 (02) :387-397