Impairment of muscarinic stimulation of adenylyl cyclase by heparin in rat olfactory bulb

In rat olfactory bulb membranes, the stimulation of adenylyl cyclase by the cholinergic agonist carbachol (CCh) was markedly inhibited by heparin at concentrations (0.3-10 microM) that had smaller or no effects on the enzyme stimulations elicited by vasoactive intestinal peptide, pituitary adenylate cyclase activating polypeptide (PACAP), 1-isoproterenol and corticotropin releasing hormone. Heparin did not significantly affect the binding of [3H]N-methylscopolamine ([3H]NMS) to muscarinic receptors, but decreased the potency of CCh in displacing the bound radioligand in a manner similar to that of the GTP analogue guanosine-5'-O-(3'-thio)triphosphate (GTPgammaS). Heparin inhibited the binding of [35S]GTPgammaS to membrane G proteins stimulated by CCh more potently than that elicited by PACAP. Moreover, at the same concentrations, heparin inhibited the muscarinic inhibition of adenylyl cyclase in rat striatal membranes. These data indicate that heparin impairs the muscarinic stimulation of olfactory bulb adenylyl cyclase likely by interfering with the receptor-induced activation of G proteins. The higher sensitivity to heparin of this response as compared to those displayed by Gs-mediated enzyme stimulations provides further evidence that Gi/Go, rather than Gs, mediate the muscarinic stimulation of adenylyl cyclase in rat olfactory bulb.