Title

Structural Determinants For Antagonist Pharmacology That Distinguish The ρ1 Gabac Receptor From Gabaa Receptors

Department

neurobiology

Document Type

Article

Abstract

GABA receptor (GABAR) types C (GABACR) and A (GABAAR) are both GABA-gated chloride channels that are distinguished by their distinct competitive antagonist properties. The structural mechanism underlying these distinct properties is not well understood. In this study, using previously identified binding residues as a guide, we made individual or combined mutations of nine binding residues in the ρ1 GABACR subunit to their counterparts in the α1β2γ 2 GABAAR or reverse mutations in α1 or β2 subunits. The mutants were expressed in Xenopus laevis oocytes and tested for sensitivities of GABA-induced currents to the GABA A and GABAC receptor antagonists. The results revealed that bicuculline insensitivity of the ρ1 GABACR was mainly determined by Tyr106, Phe138 and Phe240 residues.Gabazine insensitivity of the ρ1 GABACR was highly dependent on Tyr102, Tyr106, and Phe138. The sensitivity of the ρ1 GABACR to 3-aminopropyl-phosphonic acid and its analog 3-aminopropyl-(methyl)phosphinic acid mainly depended on residues Tyr102, Val140, FYS240-242, and Phe138. Thus, the residues Tyr102, Tyr106, Phe138, and Phe240 in the ρ1 GABACR are major determinants for its antagonist properties distinct from those in the GABAAR. In addition, Val140 in the GABA CR contributes to 3-APA binding. In conclusion, we have identified the key structural elements underlying distinct antagonist properties for the GABACR. The mechanistic insights were further extended and discussed in the context of antagonists docking to the homology models of GABAA or GABAC receptors. Copyright © 2008 The American Society for Pharmacology and Experimental Therapeutics.

Publication Date

10-1-2008

Publication Title

Molecular Pharmacology

ISSN

0026895X

Volume

74

Issue

4

First Page

941

Last Page

951

Digital Object Identifier (DOI)

10.1124/mol.108.048710

This document is currently not available here.

Share

COinS