Pharmacology of recombinant γ‐aminobutyric acidA receptors rendered diazepam‐insensitive by point‐mutated α‐subunits

FEBS Letters

Mohler, Hanns¹  Löw, Karin¹  Benson, Jack A¹  Rudolph, Uwe¹  Keist, Ruth¹ 

[1] Institute of Pharmacology, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland

关键词: Neurotransmitter;    Receptor;    γ-Aminobutyric acid;    Benzodiazepine;    Recombinant;    Central nervous system;    GABAA;    γ-aminobutyric acid type A;    BZ;    benzodiazepine;    Ro 15-4513;    ethyl-8-azido-5;    6-dihydro-5-methyl-6-oxo-4H-imidazo[1;    5-a][1;    4]benzodiazepine-3-carboxylate;    DMCM;    methyl-6;    7-dimethoxy-4-ethyl-β-carboline-3-carboxylate;   

DOI  :  10.1016/S0014-5793(98)00803-5

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Amino acids in the α- and γ-subunits contribute to the benzodiazepine binding site of GABA_A-receptors. We show that the mutation of a conserved histidine residue in the N-terminal extracellular segment (α1^H101R, α2^H101R, α3^H126R, and α5^H105R) results not only in diazepam-insensitivity of the respective αxβ2,3γ2-receptors but also in an increased potentiation of the GABA-induced currents by the partial agonist bretazenil. Furthermore, Ro 15-4513, an inverse agonist at wild-type receptors, acts as an agonist at all mutant receptors. This conserved molecular switch can be exploited to identify the pharmacological significance of specific GABA_A-receptor subtypes in vivo.

【 授权许可】

Unknown