BIMODAL REGULATION OF CYCLIC-AMP BY MUSCARINIC RECEPTORS - INVOLVEMENT OF MULTIPLE G-PROTEINS AND DIFFERENT FORMS OF ADENYLYL-CYCLASE

In membranes of rat olfactory bulb, muscarinic receptor agonists stimulate basal adenylyl cyclase activity. This response is inhibited by a number of muscarinic receptor antagonists with a rank order of potency suggesting the involvement of the M(4) muscarinic receptor subtype. The stimulatory effect does not require Ca2+ and occurs independently of activation of phosphoinositide hydrolysis. Pretreatment with pertussis toxin completely prevents the muscarinic stimulation of adenylyl cyclase, indicating the participation of G proteins of the Gi/Go family. Immunological impairment of the G protein, G(s), also reduces the muscarinic response, whereas concomitant activation of G(s)-coupled receptors by CRH or VIP results in a synergistic stimulation of adenylyl cyclase activity. Although these data suggest a role for G(s), a body of evidence indicates that the muscarinic receptors do not interact directly with this G protein. Moreover, the Ca2+/calmodulin (Ca2+/CaM)- and forskolin-stimulated enzyme activities are inhibited by muscarinic receptor activation in a pertussis toxin -sensitive manner and with a pharmacological profile similar to that observed for the stimulatory response. These data indicate that in rat olfactory bulb M(4) muscarinic receptors exert a bimodal control on cyclic AMP formation through a sequence of events that may involve activation of G(i)/G(o) proteins, synergistic interaction with G(s) and differential modulation of Ca2+/CaM-independent and -dependent forms of adenylyl cyclase.