RT Journal Article
SR Electronic
T1 Involvement of a high-affinity GTPase in the inhibitory coupling of striatal muscarinic receptors to adenylate cyclase.
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 380
OP 386
VO 24
IS 3
A1 P Onali
A1 M C Olianas
A1 J P Schwartz
A1 E Costa
YR 1983
UL http://molpharm.aspetjournals.org/content/24/3/380.abstract
AB 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.