Immediate and delayed consequences of xanomeline wash-resistant binding at the M3 muscarinic receptor

Meredith J. Noetzel; Marianne K.O. Grant; Esam E. El-Fakahany

doi:10.1007/s11064-008-9886-3

Immediate and delayed consequences of xanomeline wash-resistant binding at the M3 muscarinic receptor

Meredith J. Noetzel, Marianne K.O. Grant, Esam E. El-Fakahany

Experimental and Clinical Pharmacology

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Xanomeline is thought to be a M1/M4 functionally selective agonist at muscarinic receptors. We have previously demonstrated that it binds in a unique manner at the M1 receptor. In the current study, we examined the ability of xanomeline to bind to the M3 receptor and determined the long-term consequences of this mode of binding in Chinese hamster ovary cells expressing M3 receptors. Xanomeline binds in a reversible and wash-resistant manner at the M3 receptor and elicits a functional response under both conditions. Long-term exposure to xanomeline resulted in changes in the binding profile of [³H]NMS and a decrease in cell-surface receptor density. Additionally, pretreatment with xanomeline was associated with antagonism of the functional response to subsequent stimulation by conventional agonists. Our results indicate that xanomeline binds to and activates the M3 muscarinic receptor in a wash-resistant manner, and that this type of binding results in time-dependent receptor regulation.

Original language	English (US)
Pages (from-to)	1138-1149
Number of pages	12
Journal	Neurochemical Research
Volume	34
Issue number	6
DOIs	https://doi.org/10.1007/s11064-008-9886-3
State	Published - Jun 2009

Bibliographical note

Funding Information:
Acknowledgments This work was supported by National Institutes of Health Grant NS25743. The project described was also supported by Grant Number T32DE007288 from the National Institute of Dental & Craniofacial Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Dental & Craniofacial Research or the National Institutes of Health.

Keywords

CHO cells
Muscarinic receptors
Receptor binding and inositol phosphates
Xanomeline

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abstract = "Xanomeline is thought to be a M1/M4 functionally selective agonist at muscarinic receptors. We have previously demonstrated that it binds in a unique manner at the M1 receptor. In the current study, we examined the ability of xanomeline to bind to the M3 receptor and determined the long-term consequences of this mode of binding in Chinese hamster ovary cells expressing M3 receptors. Xanomeline binds in a reversible and wash-resistant manner at the M3 receptor and elicits a functional response under both conditions. Long-term exposure to xanomeline resulted in changes in the binding profile of [3H]NMS and a decrease in cell-surface receptor density. Additionally, pretreatment with xanomeline was associated with antagonism of the functional response to subsequent stimulation by conventional agonists. Our results indicate that xanomeline binds to and activates the M3 muscarinic receptor in a wash-resistant manner, and that this type of binding results in time-dependent receptor regulation.",

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Immediate and delayed consequences of xanomeline wash-resistant binding at the M3 muscarinic receptor

Abstract

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