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NEUROPHARMACOLOGY

Identification of Structures within GABA_A Receptor Subunits That Regulate the Agonist Action of Pentobarbital

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

Barbiturates act on GABA_A receptors (GABARs) through three distinct mechanisms, resulting in positive allosteric modulation, direct activation, and inhibition. These effects are observed at different concentrations and are differentially affected by some mutations and by the receptor's subunit composition. Mammalian GABARs can be formed from a combination of 16 different subunit subtypes. Although the effect of barbiturates depends largely on the subunit, their agonist activity is substantially influenced by the subunit subtype. Pentobarbital is a more effective agonist than GABA only when receptors contain an 6 subunit. Results from chimeric 1/6 subunits suggested that structural differences within the extracellular N-terminal domain were responsible for this characteristic. 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 effect of the mutation on direct activation by pentobarbital was determined with whole-cell electrophysiological recordings. Our results indicate that only one of these mutations, 6(T69K), altered pentobarbital efficacy. This single mutation reduced the response to pentobarbital to a level intermediate to the wild-type 112L and 612L isoforms. The mutation did not affect the sensitivity of the receptor to GABA but did reduce the efficacy of etomidate, another i.v. anesthetic with activity similar to pentobarbital. The reverse mutation in the 1 subunit (K70T) did not alter the response to pentobarbital. This is the first identification of a structural difference in GABAR subtypes that regulates direct activation by barbiturates.

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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