title: Kinetics of tert-[35S]butylbicyclophosphorothionate binding in the cerebral cortex of newborn and adult rats: effects of GABA and receptor desensitization.
abstract: The effects of GABA on the kinetics of tert-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding to the convulsant site of GABAA receptors were studied in membrane suspensions from the cerebral cortex of newborn (1-day-old) and adult (90-day-old) rats. TBPS dissociation was biphasic in neonates and adults, indicating that more than one interconvertible state of [35S]TBPS binding sites may be present in the cerebral cortex. In the absence of GABA, the fast (t1/2, 11 min) and slow (t1/2, 77 min) components of TBPS dissociation in newborn rats were approximately fourfold slower than in adults. The acceleration of the dissociation rates caused by 2 microM GABA, however, was more robust in neonates than in adults (six- to ninefold vs. twofold increase, respectively). Moreover, the dissociation rates of TBPS in membranes preincubated with 2 microM GABA (dissociation started by adding 40 microM picrotoxin) were two- to fourfold slower than in membranes preincubated without GABA (dissociation started by adding 40 microM picrotoxin plus 2 microM GABA). Taken together, these results suggest that (1) the closed state of GABAA receptors is associated with a more effective steric barrier for the binding of TBPS in neonates compared with adults, (2) GABA produces a larger acceleration of the binding kinetics of TBPS in neonates than in adults, and (3) long incubations with GABA may cause receptor desensitization, which in turn slows down the dissociation rates of TBPS.
authors.affiliation: Department of Toxicology, University of Cagliari, Cagliari, Italy.
authors.forename: O
authors.initials: O
authors.lastname: Giorgi
authors.forename: M
authors.initials: M
authors.lastname: Orlandi
authors.forename: D
authors.initials: D
authors.lastname: Lecca
authors.forename: G P
authors.initials: GP
authors.lastname: Serra
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: M G
authors.initials: MG
authors.lastname: Corda
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism* / Q000494:pharmacology; D002540:Cerebral Cortex / Q000737:chemistry* / Q000378:metabolism; D003292:Convulsants / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D007700:Kinetics; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000378:metabolism*; D012680:Sensitivity and Specificity; D013462:Sulfur Radioisotopes / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants; D008565:Membrane Proteins; D018079:Receptors, GABA; D013462:Sulfur Radioisotopes; D005680:gamma-Aminobutyric Acid; C037476:tert-butylbicyclophosphorothionate