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Structural Determinants for Antagonist Pharmacology That Distinguish the ₁ GABA_C Receptor from GABA_A Receptors

Division of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona

GABA receptor (GABAR) types C (GABA_CR) and A (GABA_AR) 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 ₁ GABA_CR subunit to their counterparts in the ₁β₂₂ GABA_AR or reverse mutations in ₁ or β₂ subunits. The mutants were expressed in Xenopus laevis oocytes and tested for sensitivities of GABA-induced currents to the GABA_A and GABA_C receptor antagonists. The results revealed that bicuculline insensitivity of the ₁ GABA_CR was mainly determined by Tyr106, Phe138 and Phe240 residues. Gabazine insensitivity of the ₁ GABA_CR was highly dependent on Tyr102, Tyr106, and Phe138. The sensitivity of the ₁ GABA_CR 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 ₁ GABA_CR are major determinants for its antagonist properties distinct from those in the GABA_AR. 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 GABA_CR. The mechanistic insights were further extended and discussed in the context of antagonists docking to the homology models of GABA_A or GABA_C receptors.

Received for publication May 6, 2008.

Accepted for publication July 2, 2008.

Address correspondence to: Dr. Yongchang Chang, Division of Neurobiology, Barrow Neurological Institute, 350 West Thomas Road, Phoenix, AZ 85013. E-mail: yongchang.chang{at}chw.edu