Alkyl-substituted γ-butyrolactones act at a distinct site allosterically linked to the TBPS/picrotoxinin site on the GABAA receptor complex

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