ALKYL-SUBSTITUTED GAMMA-BUTYROLACTONES ACT AT A DISTINCT SITE ALLOSTERICALLY LINKED TO THE TBPS PICROTOXININ SITE ON THE GABA(A)RECEPTOR COMPLEX

Effects of alkyl-substituted gamma-butyrolactones and gamma-thiobutyrolactones on [S-35]t-butylbicyclophosphorothionate (S-35-TBPS) dissociation from the picrotoxinin receptor were studied. Unlike picrotoxinin, these lactones accelerated the dissociation rate of S-35-TBPS. Thus, previous reports that these lactones change the K(d) but not the B(max) of S-35-TBPS in equilibrium binding experiments is explained not by competitive inhibition, but by an allosteric interaction with the S-35-TBPS binding site. These results indicate that modulatory effects of alkyl-substituted gamma-butyrolactones may result from their action at a distinct site on the gamma-aminobutyric acid (GABA)A receptor.