SYNERGISTIC INTERACTION OF MUSCARINIC AND OPIOID RECEPTORS WITH G(S)-LINKED NEUROTRANSMITTER RECEPTORS TO STIMULATE ADENYLYL-CYCLASE ACTIVITY OF RAT OLFACTORY-BULB

We reported previously that in homogenates of rat olfactory bulb musca rinic and opioid receptor agonists stimulate adenylyl cyclase activity . In the present study we show that carbachol (CCh) and Leu-Enkephalin act synergistically with vasoactive intestinal peptide (VIP) and cort icotropin-releasing hormone (CRH), but not with l-isoproterenol, in in creasing cyclic AMP formation. The synergistic interaction consists of an increase in the maximal adenylyl cyclase activation without a sign ificant change in the potency of each agonist. CCh also fails to affec t I-125-CRH binding to olfactory bulb membranes. The synergism require s micromolar concentrations of GTP. Substitution of the stable GTP ana log guanosine 5'-O-3'-thiotriphosphate) for GTP allows the CRH stimula tion, but abolishes the CCh enhancement of both basal and CRH-stimulat ed enzyme activities. Moreover, in vivo treatment of olfactory bulbs w ith pertussis toxin completely prevents the muscarinic and opioid effe cts. Thus, the synergistic interaction appears to result from opioid- and muscarinic-induced activation of a pertussis toxin-sensitive GTP-b inding protein which may potentiate the adenylyl cyclase stimulation b y the stimulatory GTP-binding protein activated by either VIP or CRH r eceptors.