TY - JOUR T1 - Structural Determinants for Antagonist Pharmacology That Distinguish the ρ<sub>1</sub> GABA<sub>C</sub> Receptor from GABA<sub>A</sub> Receptors JF - Molecular Pharmacology JO - Mol Pharmacol SP - 941 LP - 951 DO - 10.1124/mol.108.048710 VL - 74 IS - 4 AU - Jianliang Zhang AU - Fenqin Xue AU - Yongchang Chang Y1 - 2008/10/01 UR - http://molpharm.aspetjournals.org/content/74/4/941.abstract N2 - 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 α1β2γ2 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 GABAA 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 GABACR 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. The American Society for Pharmacology and Experimental Therapeutics ER -