Involvement of a high-affinity GTPase in the inhibitory coupling of striatal muscarinic receptors to adenylate cyclase.
The stimulation of GTP hydrolysis has been proposed as a mechanism by which hormones inhibit receptor-coupled adenylate cyclase activity. The present study attempts to verify whether this mechanism is also operative in transmitter-mediated receptor-coupled attenuation of adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] located in synaptic plasma membrane preparations. As a model, we used the inhibition of adenylate cyclase activity by muscarinic receptor activation in rat striatum. This striatal preparation contains high-affinity GTPase (EC 3.6.1-) activity which is stimulated when the recognition site for muscarinic agonists is occupied. Acetylcholine (ACh), but not nicotine, increases the Vmax of the high-affinity GTPase, and the stimulatory effect is antagonized by atropine but not by d-tubocurarine. The rank order of potency of various cholinergic agonists to stimulate GTPase correlates with their ability to inhibit adenylate cyclase activity of striatal membranes. Pre-exposure of striatal membranes to guanosine-5'-O-(3-thiotriphosphate) causes a parallel decrease in the basal and ACh-stimulated GTPase activities and in the ACh-induced inhibition of adenylate cyclase. Treatment of the membranes with cholera toxin does not affect the ACh-stimulated GTPase activity but amplifies the extent of adenylate cyclase inhibition elicited by the cholinergic agonist. These results indicate that the stimulation of a high-affinity GTPase parallels the inhibitory coupling of central muscarinic receptors to adenylate cyclase.
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002772:Cholera Toxin / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D010277:Parasympathomimetics / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism*
D010277:Parasympathomimetics; D011976:Receptors, Muscarinic; D006165:Guanylyl Imidodiphosphate; D006160:Guanosine Triphosphate; D002772:Cholera Toxin; D010744:Phosphoric Monoester Hydrolases; D020558:GTP Phosphohydrolases; D000262:Adenylyl Cyclases