Structural Determinants For Antagonist Pharmacology That Distinguish The Ï1 Gabac Receptor From Gabaa Receptors
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 Ï1 GABACR subunit to their counterparts in the Î±1Î²2Î³ 2 GABAAR or reverse mutations in Î±1 or Î²2 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 Ï1 GABACR was mainly determined by Tyr106, Phe138 and Phe240 residues.Gabazine insensitivity of the Ï1 GABACR was highly dependent on Tyr102, Tyr106, and Phe138. The sensitivity of the Ï1 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 Ï1 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 Â© 2008 The American Society for Pharmacology and Experimental Therapeutics.
Digital Object Identifier (DOI)
Zhang, Jianliang; Xue, Fenqin; and Chang, Yongchang, "Structural Determinants For Antagonist Pharmacology That Distinguish The Ï1 Gabac Receptor From Gabaa Receptors" (2008). Translational Neuroscience. 66.