Identification of structures within GABAA receptor alpha subunits that regulate the agonist action of pentobarbital

Barbiturates act on GABAA 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. Mamma-lian 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