Muscarinic acetylcholine receptors linked to the inhibition of adenylate cyclase activity in membranes from the rat striatum and myocardium can be distinguished on the basis of agonist efficacy.
Muscarinic agonists produce an inhibition of adenylate cyclase activity in broken cell preparations from rat striatum and myocardium. We have attempted to determine the occupancy-response relationships of three muscarinic agonists (carbachol, arecoline, and pilocarpine) by comparing their dose-response curves in these preparations with occupancy curves obtained under the same conditions. These comparisons suggest that the occupancy-response relationships for all three agonists in myocardium and for arecoline and pilocarpine in striatum are linear, response being directly proportional to occupancy. However, there appears to be a considerable receptor reserve for carbachol in the striatum, with carbachol producing a 50% maximal response at concentrations that occupy only 3% of the striatal receptors. These postulated occupancy-response relationships have been tested by blocking different proportions of the muscarinic receptors with the irreversible antagonist benzilylcholine mustard. The effects of this blockade on the dose-response curves are as predicted from the occupancy-response relationships, suggesting that these relationships are correct. The relative efficacies of these muscarinic agonists can be determined from their occupancy-response relationships. The efficacies of arecoline and pilocarpine relative to carbachol are approximately 0.13 and approximately 0.03 in striatum and approximately 1.0 and approximately 0.45 in myocardium, respectively. This difference in relative efficacies in the two tissues is evidence of a real conformational difference between the muscarinic receptors linked to adenylate cyclase in these preparations.
Keen
M
M
Department of Pharmacology and Therapeutics, University of Leicester, United Kingdom.
Nahorski
S R
SR
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D002794:Choline / Q000031:analogs & derivatives / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D010276:Parasympatholytics / Q000494:pharmacology; D010277:Parasympathomimetics / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*
D000067956:Adenylyl Cyclase Inhibitors; D010276:Parasympatholytics; D010277:Parasympathomimetics; D011976:Receptors, Muscarinic; C100238:benzilylcholine mustard; D002794:Choline