Benson J A, Löw K, Keist R, Mohler H, Rudolph U
Institute of Pharmacology, University of Zürich, Switzerland.
FEBS Lett. 1998 Jul 24;431(3):400-4. doi: 10.1016/s0014-5793(98)00803-5.
Amino acids in the alpha- and gamma-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 (alpha1H101R, alpha2H101R, alpha3H126R, and alpha5H105R) results not only in diazepam-insensitivity of the respective alphaxbeta2,3gamma2-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.
α亚基和γ亚基中的氨基酸对GABA（A）受体的苯二氮䓬结合位点有贡献。我们发现，N端细胞外区段中一个保守组氨酸残基的突变（α1H101R、α2H101R、α3H126R和α5H105R）不仅导致相应的αxβ2,3γ2受体对安定不敏感，而且还导致部分激动剂bretazenil对GABA诱导电流的增强作用增加。此外，Ro 15-4513作为野生型受体的反向激动剂，在所有突变受体上均表现为激动剂。这种保守的分子开关可用于在体内确定特定GABA（A）受体亚型的药理学意义。
