title: Positive regulation of GABA(B) receptors dually coupled to cyclic AMP by the allosteric agent CGP7930.
abstract: The ability of 2,6 Di-tert-butyl-4-(-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930), a positive allosteric modulator of GABA(B) receptors, to regulate GABA(B) receptor-induced stimulation and inhibition of adenylyl cyclase activity in rat brain was investigated. In olfactory bulb granule cell layer and in frontal cortex, CGP7930 potentiated the stimulatory effects of (-)-baclofen and gamma-aminobutyric acid (GABA) on basal and corticotropin-releasing hormone-stimulated adenylyl cyclase activities, respectively. In these stimulatory responses, CGP7930 enhanced both agonist potencies and maximal effects. When GABA(B) receptor-mediated inhibition of forskolin-stimulated adenylyl cyclase activity of frontal cortex was examined, CGP7930 increased the agonist potencies but failed to affect the maximal effect of (-)-baclofen and modestly increased that of GABA. Similar results were obtained for the inhibition of Ca(2+)/calmodulin-stimulated adenylyl cyclase in striatum and cerebellum. Western blot analysis of each membrane preparation showed the presence of GABA(B2) receptor subunit, a putative site of action of CGP7930. These data indicate that CGP7930 positively modulates brain GABA(B) receptors coupled to either stimulation or inhibition of cyclic AMP signalling.
authors.affiliation: Section of Biochemical Pharmacology, Department of Neuroscience, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Cagliari, Italy. onali@unica.it
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Onali
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Mascia
authors.forename: Maria C
authors.initials: MC
authors.lastname: Olianas
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000494:Allosteric Regulation / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D001418:Baclofen / Q000008:administration & dosage / Q000493:pharmacokinetics; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D005576:Colforsin / Q000493:pharmacokinetics; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism / Q000493:pharmacokinetics; D000242:Cyclic AMP / Q000096:biosynthesis / Q000378:metabolism*; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D005625:Frontal Lobe / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D015870:Gene Expression; D008297:Male; D009830:Olfactory Bulb / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010636:Phenols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000096:biosynthesis / Q000276:immunology; D018080:Receptors, GABA-B / Q000187:drug effects* / Q000378:metabolism*; D015398:Signal Transduction; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: C438607:2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol; D002147:Calmodulin; C116566:Gabbr2 protein, rat; D010636:Phenols; D018079:Receptors, GABA; D018080:Receptors, GABA-B; D005576:Colforsin; D005680:gamma-Aminobutyric Acid; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D001418:Baclofen