Alkyl-substituted gamma-butyrolactones act at a distinct site allosterically linked to the TBPS/picrotoxinin site on the GABAA receptor complex.
Effects of alkyl-substituted gamma-butyrolactones and gamma-thiobutyrolactones on [35S]t-butylbicyclophosphorothionate (35S-TBPS) dissociation from the picrotoxinin receptor were studied. Unlike picrotoxinin, these lactones accelerated the dissociation rate of 35S-TBPS. Thus, previous reports that these lactones change the Kd but not the Bmax of 35S-TBPS in equilibrium binding experiments is explained not by competitive inhibition, but by an allosteric interaction with the 35S-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.
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110.
K D
KD
Holland
M G
MG
Bouley
D F
DF
Covey
J A
JA
Ferrendelli
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D007700:Kinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*; D013462:Sulfur Radioisotopes
D011963:Receptors, GABA-A; D013462:Sulfur Radioisotopes; C037480:picrotoxinin receptor; C041598:t-butylbicyclophosphorothionate receptor; C083047:gamma-thiobutyrolactone; D015107:4-Butyrolactone