MUTATION OF AN ARGININE RESIDUE IN THE HUMAN GLYCINE RECEPTOR TRANSFORMS BETA-ALANINE AND TAURINE FROM AGONISTS INTO COMPETITIVE ANTAGONISTS

被引:138
作者
RAJENDRA, S [1 ]
LYNCH, JW [1 ]
PIERCE, KD [1 ]
FRENCH, CR [1 ]
BARRY, PH [1 ]
SCHOFIELD, PR [1 ]
机构
[1] GARVAN INST MED RES,DARLINGHURST,NSW 2010,AUSTRALIA
基金
英国医学研究理事会;
关键词
D O I
10.1016/0896-6273(95)90251-1
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Agonist binding to the inhibitory glycine receptor (GlyR) initiates the opening of a chloride-selective channel that modulates the neuronal membrane potential. Point mutations of the GlyR, substituting Arg-271 with either Leu or Gin, have been shown to underlie the inherited neurological disorder startle disease (hyperekplexia). We show that these substitutions result in the redistribution of GlyR single-channel conductances to lower conductance levels. Additionally, the binding of the glycinergic agonists beta-alanine and taurine to mutated GryRs does not initiate a chloride current, but instead competitively antagonizes currents activated by glycine. These findings are consistent with mutations of Arg-271 resulting in the uncoupling of the agonist binding process from the channel activation mechanism of the receptor.
引用
收藏
页码:169 / 175
页数:7
相关论文
共 40 条
[1]   CONTRIBUTION OF CHLORIDE SHIFTS TO THE FADE OF GAMMA-AMINOBUTYRIC ACID-GATED CURRENTS IN FROG DORSAL-ROOT GANGLION-CELLS [J].
AKAIKE, N ;
INOMATA, N ;
TOKUTOMI, N .
JOURNAL OF PHYSIOLOGY-LONDON, 1987, 391 :219-234
[2]   GABA(A) RECEPTOR NEEDS 2 HOMOLOGOUS DOMAINS OF THE BETA-SUBUNIT FOR ACTIVATION BY GABA BUT NOT BY PENTOBARBITAL [J].
AMIN, J ;
WEISS, DS .
NATURE, 1993, 366 (6455) :565-569
[3]   STARTLE DISORDERS OF MAN - HYPEREKPLEXIA, JUMPING AND STARTLE EPILEPSY [J].
ANDERMANN, F ;
ANDERMANN, E .
BRAIN & DEVELOPMENT, 1988, 10 (04) :213-222
[5]   UNCONVENTIONAL PHARMACOLOGY OF A NEURONAL NICOTINIC RECEPTOR MUTATED IN THE CHANNEL DOMAIN [J].
BERTRAND, D ;
DEVILLERSTHIERY, A ;
REVAH, F ;
GALZI, JL ;
HUSSY, N ;
MULLE, C ;
BERTRAND, S ;
BALLIVET, M ;
CHANGEUX, JP .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (04) :1261-1265
[6]   RESIDUES WITHIN TRANSMEMBRANE SEGMENT M2 DETERMINE CHLORIDE CONDUCTANCE OF GLYCINE RECEPTOR HOMO-OLIGOMERS AND HETEROOLIGOMERS [J].
BORMANN, J ;
RUNDSTROM, N ;
BETZ, H ;
LANGOSCH, D .
EMBO JOURNAL, 1993, 12 (10) :3729-3737
[7]  
CASCIO M, 1993, J BIOL CHEM, V268, P22135
[8]   HIGH-EFFICIENCY TRANSFORMATION OF MAMMALIAN-CELLS BY PLASMID DNA [J].
CHEN, C ;
OKAYAMA, H .
MOLECULAR AND CELLULAR BIOLOGY, 1987, 7 (08) :2745-2752
[9]   MOLECULAR PHARMACOLOGY - THE BINDING ISSUE [J].
COLQUHOUN, D ;
FARRANT, M .
NATURE, 1993, 366 (6455) :510-511
[10]   FUNCTIONAL ARCHITECTURE OF THE NICOTINIC ACETYLCHOLINE-RECEPTOR - A PROTOTYPE OF LIGAND-GATED ION CHANNELS [J].
DEVILLERSTHIERY, A ;
GALZI, JL ;
EISELE, JL ;
BERTRAND, S ;
BERTRAND, D ;
CHANGEUX, JP .
JOURNAL OF MEMBRANE BIOLOGY, 1993, 136 (02) :97-112