title: Differential receptor-G-protein coupling evoked by dissimilar cannabinoid receptor agonists.
abstract: Multiple affinity states are revealed by agonist competition for radioantagonist [3H]SR141716A binding to rat brain CB1 cannabinoid receptors. Desacetyllevonantradol (DALN), a tricyclic cannabinoid, and WIN55212-2, an aminoalkylindole, both bound in two discrete affinity states (30% high affinity), but the ratios of the IC50 revealed distinct differences. Other affinity-state differences between the agonists were: Na+ reduced the affinity for the membrane-bound receptor by 10-fold for DALN but minimally for WIN55212-2; a nonhydrolysable GTP analogue decreased the fraction of high-affinity WIN55212-2 binding but not that of DALN unless Na+ was also present. Detergent solubilisation increased the fraction of high-affinity binding for both agonists but eliminated any effect of Na+ on the agonist affinities. In detergent solution, the GTP analogue reduced the WIN55212-2 high-affinity fraction but not that of DALN, even though the IC50 values increased for both DALN and WIN55212-2. The differential modulation of CB1 receptor-G-protein coupling by Na+ and guanine nucleotides is dependent upon the cannabimimetic agonist bound.
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, Missouri 63104, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Houston
authors.forename: A C
authors.initials: AC
authors.lastname: Howlett
mesh_terms: D000818:Animals; D048588:Benzoxazines; D001665:Binding Sites; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002186:Cannabinoids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D066298:In Vitro Techniques; D009025:Morpholines / Q000378:metabolism; D009281:Naphthalenes / Q000378:metabolism; D010617:Phenanthridines / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism; D011720:Pyrazoles / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists* / Q000378:metabolism*; D000077285:Rimonabant; D012964:Sodium / Q000494:pharmacology
chemical_list: D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D010617:Phenanthridines; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C032426:desacetylnantradol; D012964:Sodium; D019204:GTP-Binding Proteins; D000077285:Rimonabant