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NEUROPHARMACOLOGY

Structural Determinants of the Pharmacological Properties of the GABA_A Receptor 6 Subunit

Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina

GABA_A receptors are responsible for fast inhibitory neurotransmission in the mammalian brain and are the targets for many clinical drugs that act as antiepileptics, anxiolytics, and sedatives. The pharmacological characteristics of the receptor are largely determined by its subunit composition. Compared with all other subtypes, the 6 subtype confers unique pharmacological properties. In particular, 6-containing receptors are more sensitive to both the agonist GABA and the antagonist amiloride. Results from chimeric constructs of the 1 and 6 subunits suggested that structural differences within the extracellular N-terminal domain were responsible for both these characteristics. Within this domain, we examined 15 amino acid residues unique to the 6 subtype. Each of these sites was individually mutated in the 6 subunit to the corresponding residue of the 1 subunit. The mutated subunits were expressed in human embryonic kidney-293T cells along with wild-type 3 and 2L subunits and sensitivity to GABA and amiloride determined with whole-cell electrophysiological recordings. Serine83 in the 6 subunit influenced sensitivity to both GABA and amiloride. Leucine174 and tyrosine175 were also found to contribute to inhibition by amiloride but did not affect GABA sensitivity. These structural differences are at least partly responsible for the unique pharmacological properties associated with the 6 subunit.

Address correspondence to: Dr. Janet L. Fisher, Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC 29208. E-mail: jfisher{at}med.sc.edu

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