Evidence for different interactions between beta(1)- and beta(2)-adrenoceptor subtypes with adenylyl cyclase in the rat brain: a concentration-response study using forskolin.
The aim of this study was to investigate beta(1)- and beta(2)-adrenoceptor signalling systems in the rat brain studying the synergistic effects between beta-adrenoceptor agonists and forskolin- induced activation of adenylyl cyclase. Experiments were performed in slices from cerebral cortex and cerebellum because they contain mainly beta(1)- and almost exclusively beta(2)- adrenoceptors, respectively. Five beta-adrenergic agonists were used, clenbuterol, flerobuterol, isoproterenol, salbutamol, and tulobuterol. All agonists stimulated cyclic AMP accumulation in the cerebral cortex but flerobuterol was inactive in the cerebellum. Forskolin amplified the generation of cyclic AMP. Forskolin potentiation was observed in glial cells but not in neurons and was not dependent on the number of beta-adrenoceptors. In return the amplitude of the potentiation was highly dependent on the intrinsic activity of the agonist in the cerebral cortex whereas it was constant whatever the agonist tested in the cerebellum. To analyse this difference we developed a modelling approach using a concentration-response study. Isoproterenol and forskolin stimulations of cyclic AMP production were studied either alone or in combination with increasing concentrations of forskolin and isoproterenol, respectively. In the cerebral cortex isoproterenol and forskolin were both able to potentiate the cyclic AMP accumulation induced by the other compound, whereas, in the cerebellum, isoproterenol was unable to increase the stimulation induced by forskolin. The results support the hypothesis that beta(1)- and beta(2)-adrenoceptors display distinct mechanisms of action in the signalling system by which they stimulate the accumulation of cyclic AMP.
Morin
D
D
Laboratoire de Pharmacologie, Faculté de Médecine de Paris XII, 8 rue du Général Sarrail, Creteil, F-94010, France.
Sapena
R
R
Tillement
J P
JP
Urien
S
S
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000465:Algorithms; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001921:Brain / Q000201:enzymology; D001923:Brain Chemistry / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008962:Models, Theoretical; D017933:Peripheral Nervous System / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects*; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D000929:Antidepressive Agents, Tricyclic; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D005576:Colforsin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D003891:Desipramine