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J. Biol. Chem., Vol. 276, Issue 42, 38934-38939, October 19, 2001

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₄₃ GABA_A Receptors Characterized by Fluorescence Resonance Energy Transfer-derived Measurements of Membrane Potential^*

Charles E. Adkins, Gopalan V. Pillai, Julie Kerby, Timothy P. Bonnert, Christine Haldon, Ruth M. McKernan, Jesus E. Gonzalez^§, Kahuku Oades^§, Paul J. Whiting, and Peter B. Simpson

From the Neuroscience Research Centre, Terlings Park, Merck Sharp & Dohme, Eastwick Road, Harlow, Essex, United Kingdom CM20 2QR and ^§ Aurora Biosciences Corp., La Jolla, California 92121

Selective modulators of -aminobutyric acid, type A (GABA_A) receptors containing ₄ subunits may provide new treatments for epilepsy and premenstrual syndrome. Using mouse L(tk) cells, we stably expressed the native GABA_A receptor subunit combinations _{332, 432}, and, for the first time, ₄₃ and characterized their properties using a novel fluorescence resonance energy transfer assay of GABA-evoked depolarizations. GABA evoked concentration-dependent decreases in fluorescence resonance energy transfer that were blocked by GABA_A receptor antagonists and, for ₃₃₂ and ₄₃₂ receptors, modulated by benzodiazepines with the expected subtype specificity. When combined with ₄ and ₃,  subunits, compared with ₂, conferred greater sensitivity to the agonists GABA, 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol (THIP), and muscimol and greater maximal efficacy to THIP. ₄₃ responses were markedly modulated by steroids and anesthetics. Alphaxalone, pentobarbital, and pregnanolone were all 3-7-fold more efficacious at ₄₃ compared with _432. The fluorescence technique used in this study has proven valuable for extensive characterization of a novel GABA_A receptor. For GABA_A receptors containing ₄ subunits, our experiments reveal that inclusion of  instead of ₂ subunits can increase the affinity and in some cases the efficacy of agonists and can increase the efficacy of allosteric modulators. Pregnanolone was a particularly efficacious modulator of ₄₃ receptors, consistent with a central role for this subunit combination in premenstrual syndrome.

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