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Dissociation of [ 35 S] t ‐Butylbicyclophosphorothionate Binding Differentiates Convulsant and Depressant Drugs that Modulate GABAergic Transmission
Author(s) -
Maksay G.,
Ticku M. K.
Publication year - 1985
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1985.tb05439.x
Subject(s) - convulsant , convulsants , chemistry , allosteric regulation , picrotoxin , stereochemistry , depressant , dissociation (chemistry) , pharmacology , biophysics , gabaa receptor , receptor , biochemistry , neuroscience , anticonvulsant , epilepsy , biology , organic chemistry
The dissociation of [ 35 S] t ‐butylbicyclophosphorothionate ([ 35 S]TBPT) from binding sites on membranes from rat cerebral cortex, after addition of saturating concentrations of convulsant and depressant drugs, was studied. The addition of unlabeled TBPT, picrotoxinin, or pentamethylenetetrazol resulted in dissociation patterns that were monophasic and not distinguishable, suggesting that these convulsants bind competitively to the same (convulsant) sites. In contrast, γ‐aminobutyric acid (GABA) greatly facilitated [ 35 S]TBPT dissociation by binding allosterically to the GABA recognition site of the receptor‐ionophore complex. TBPT dissociation was similarly accelerated by the depressants etazolate, (+)‐etomidate, and barbiturates. The convulsant and depressant S (+) and R (‐) stereoisomers of N ‐methyl‐5‐phenyl‐5‐propyl‐barbituric acid displayed large stereoselectivity in the acceleration of TBPT dissociation. These results suggest that depressants bind to sites different from the convulsant sites of the allosteric GABA receptor complex, or the binding of depressants to the same population of sites elicits negative cooperativity and dissociates the convulsants.