The relationship between muscarinic receptor occupancy and adenylate cyclase inhibition in the rabbit myocardium

FJ Ehlert

The muscarinic receptor-binding properties of a series of muscarinic drugs were compared with their effects on adenylate cyclase in membranes of the rabbit myocardium. When measured by competitive inhibition of [3H]-N-methylscopolamine binding, the competition curves of the various agonists were adequately described by the ternary complex model. This model assumes that the receptor can bind reversibly with a guanine nucleotide binding protein in the membrane and that the affinity of the agonist for the receptor-guanine nucleotide-binding protein complex is higher than that for the free receptor. A satisfactory fit of the ternary complex model to the data could only be achieved assuming that very little receptor is precoupled with the guanine nucleotide-binding protein in the absence of agonist. There was good agreement between the efficacy of each agonist as measured by inhibition of adenylate cyclase and the estimate of the positive cooperativity between the binding of the agonist receptor complex and the guanine nucleotide-binding protein. Guanosine 5'-triphosphate (0.1 mM) had no significant effect on the binding of [3H]N-methylscopolamine but caused an increase in the concentration of the various agonists required for half-maximal receptor occupancy. There was good correlation between efficacy as measured by inhibition of adenylate cyclase and the influence of guanosine 5'-triphosphate on binding properties.

Volume 28, Issue 5, pp. 410-421, 11/01/1985
Copyright © 1985 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				F. J. Ehlert and M. T. Griffin Two-State Models and the Analysis of the Allosteric Effect of Gallamine at the M2 Muscarinic Receptor J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 1039 - 1060. [Abstract] [Full Text] [PDF]

				J. A. Tran, M. Matsui, and F. J. Ehlert Differential Coupling of Muscarinic M1, M2, and M3 Receptors to Phosphoinositide Hydrolysis in Urinary Bladder and Longitudinal Muscle of the Ileum of the Mouse J. Pharmacol. Exp. Ther., August 1, 2006; 318(2): 649 - 656. [Abstract] [Full Text] [PDF]

				M. K. O. Grant and E. E. El-Fakahany Persistent Binding and Functional Antagonism by Xanomeline at the Muscarinic M5 Receptor J. Pharmacol. Exp. Ther., October 1, 2005; 315(1): 313 - 319. [Abstract] [Full Text] [PDF]

				V. Avlani, L. T. May, P. M. Sexton, and A. Christopoulos Application of a Kinetic Model to the Apparently Complex Behavior of Negative and Positive Allosteric Modulators of Muscarinic Acetylcholine Receptors J. Pharmacol. Exp. Ther., March 1, 2004; 308(3): 1062 - 1072. [Abstract] [Full Text] [PDF]

				A. Christopoulos and T. Kenakin G Protein-Coupled Receptor Allosterism and Complexing Pharmacol. Rev., June 1, 2002; 54(2): 323 - 374. [Abstract] [Full Text] [PDF]

				D. R. Linden, M. J. Chell, E. E. El-Fakahany, and V. S. Seybold Neurokinin3 Receptors Couple to the Activation of Neuronal Nitric-Oxide Synthase in Stably Transfected Chinese Hamster Ovary Cells J. Pharmacol. Exp. Ther., May 1, 2000; 293(2): 559 - 568. [Abstract] [Full Text]

				R. M. Quock, T. H. Burkey, E. Varga, Y. Hosohata, K. Hosohata, S. M. Cowell, C. A. Slate, F. J. Ehlert, W. R. Roeske, and H. I. Yamamura The delta -Opioid Receptor: Molecular Pharmacology, Signal Transduction, and the Determination of Drug Efficacy Pharmacol. Rev., September 1, 1999; 51(3): 503 - 532. [Abstract] [Full Text] [PDF]

				D. E. Selley, Q. Liu, and S. R. Childers Signal Transduction Correlates of Mu Opioid Agonist Intrinsic Efficacy: Receptor-Stimulated [35S]GTPgamma S Binding in mMOR-CHO Cells and Rat Thalamus J. Pharmacol. Exp. Ther., May 1, 1998; 285(2): 496 - 505. [Abstract] [Full Text]

				K. A. Wreggett and J. W. Wells Cooperativity Manifest in the Binding Properties of Purified Cardiac Muscarinic Receptors J. Biol. Chem., September 22, 1995; 270(38): 22488 - 22499. [Abstract] [Full Text] [PDF]

				W. K. Vogel, V. A. Mosser, D. A. Bulseco, and M. I. Schimerlik Porcine m2 Muscarinic Acetylcholine Receptor-Effector Coupling in Chinese Hamster Ovary Cells J. Biol. Chem., June 30, 1995; 270(26): 15485 - 15493. [Abstract] [Full Text] [PDF]

				A Ashkenazi, J. Winslow, E. Peralta, G. Peterson, M. Schimerlik, D. Capon, and J Ramachandran An M2 muscarinic receptor subtype coupled to both adenylyl cyclase and phosphoinositide turnover Science, October 30, 1987; 238(4827): 672 - 675. [Abstract] [PDF]