QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.090134v1 315/1/313    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Grant, M. K. O. Articles by El-Fakahany, E. E. Search for Related Content PubMed PubMed Citation Articles by Grant, M. K. O. Articles by El-Fakahany, E. E.

CELLULAR AND MOLECULAR

Persistent Binding and Functional Antagonism by Xanomeline at the Muscarinic M₅ Receptor

Departments of Psychiatry (M.K.O.G., E.E.E.-F.), Pharmacology (E.E.E.-F.), and Neuroscience (E.E.E.-F.), University of Minnesota Medical School, Minneapolis, Minnesota

Xanomeline is a functionally selective M₁/M₄ muscarinic acetylcholine receptor agonist. We have previously identified a novel mode of interaction of this ligand with the muscarinic M₁ receptor that involves persistent binding and activation of the receptor after extensive washout. In the present study, we tested the hypothesis that xanomeline also binds in a wash-resistant manner to muscarinic receptor subtypes where it exhibits low or no efficacy, such as the M₅ receptor subtype. A secondary hypothesis is that persistent binding of xanomeline to the M₅ receptor results in wash-resistant antagonism to the effects of full agonists. These hypotheses were tested in Chinese hamster ovary cells stably expressing the M₅ receptor. In these cells, xanomeline is a weak partial agonist and is able to inhibit carbachol-induced phosphoinositide hydrolysis to the maximal response of xanomeline in a concentration-dependent manner. Pretreatment with xanomeline followed by extensive washing resulted in a significant wash-resistant reduction in receptor affinity with no significant change in maximal cell surface receptor density. This was associated with wash-resistant antagonism of carbachol-induced activation of phosphoinositide hydrolysis at the M₅ receptor, reflected as decreased carbachol potency without a change in the maximal response. Similar experiments using the partial agonist pilocarpine demonstrated a reduction of pilocarpine potency as well as maximal response. Our results clearly indicate that wash-resistant binding of xanomeline to the muscarinic M₅ receptor is accompanied by persistent antagonism of receptor function. They also suggest a relationship between the efficacy of xanomeline and the functional consequences of its wash-resistant binding at different muscarinic receptor subtypes.

Address correspondence to: Dr. Esam E. El-Fakahany, Department of Psychiatry, MMC 392, University of Minnesota Medical School, 420 Delaware St. S.E., Minneapolis, MN 55455. E-mail: elfak001{at}umn.edu

This article has been cited by other articles:

				J. A. Gray and B. L. Roth Molecular Targets for Treating Cognitive Dysfunction in Schizophrenia Schizophr Bull, September 1, 2007; 33(5): 1100 - 1119. [Abstract] [Full Text] [PDF]

				E. Machova, J. Jakubik, E. E. El-Fakahany, and V. Dolezal Wash-Resistantly Bound Xanomeline Inhibits Acetylcholine Release by Persistent Activation of Presynaptic M2 and M4 Muscarinic Receptors in Rat Brain J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 316 - 323. [Abstract] [Full Text] [PDF]

				C. Smith, T. Rahman, N. Toohey, J. Mazurkiewicz, K. Herrick-Davis, and M. Teitler Risperidone Irreversibly Binds to and Inactivates the h5-HT7 Serotonin Receptor Mol. Pharmacol., October 1, 2006; 70(4): 1264 - 1270. [Abstract] [Full Text] [PDF]

				J. Jakubik, E. E. El-Fakahany, and V. Dolezal Differences in Kinetics of Xanomeline Binding and Selectivity of Activation of G Proteins at M1 and M2 Muscarinic Acetylcholine Receptors Mol. Pharmacol., August 1, 2006; 70(2): 656 - 666. [Abstract] [Full Text] [PDF]