IMPAIRMENT OF MUSCARINIC STIMULATION OF ADENYLYL-CYCLASE BY HEPARIN IN RAT OLFACTORY-BULB

In rat olfactory bulb membranes, the stimulation of adenylyl cyclase b y the cholinergic agonist carbachol (CCh) was markedly inhibited by he parin at concentrations (0.3-10 mu M) that had smaller or no effects o n the enzyme stimulations elicited by vasoactive intestinal peptide, p ituitary adenylate cyclase activating polypeptide (PACAP), 1-isoproter enol and corticotropin releasing hormone. Heparin did not significantl y affect the binding of [H-3]N-methylscopolamine ([H-3]NMS) to muscari nic receptors, but decreased the potency of CCh in displacing the boun d radioligand in a manner similar to that of the GTP analogue guanosin e-5'-O-(3'-thio)triphosphate (GTP gamma S). Heparin inhibited the bind ing of [S-35] GTP gamma S to membrane G proteins stimulated by CCh mor e potently than that elicited by PACAP. Moreover, at the same concentr ations, heparin inhibited the muscarinic inhibition of adenylyl cyclas e in rat striatal membranes. These data indicate that heparin impairs the muscarinic stimulation of olfactory bulb adenylyl cyclase likely b y interfering with the receptor-induced activation of G proteins. The higher sensitivity to heparin of this response as compared to those di splayed by Os-mediated enzyme stimulations provides further evidence t hat Gi/Go, rather than Gs, mediate the muscarinic stimulation of adeny lyl cyclase in rat olfactory bulb.