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Xanomeline is an agonist endowed with functional preference for M 1 /M 4  muscarinic acetylcholine receptors. It also exhibits both reversible and wash-resistant binding to and activation of these receptors. So far the mechanisms of xanomeline selectivity remain unknown. To address this question we employed microfluorometric measurements of intracellular calcium levels and radioligand binding to investigate differences in the short- and long-term effects of xanomeline among muscarinic receptors expressed individually in Chinese hamster ovary cells. 1/One-min exposure of cells to xanomeline markedly increased intracellular calcium at hM 1  and hM 4 , and to a lesser extent at hM 2  and hM 3  muscarinic receptors for more than 1 hour. 2/Unlike the classic agonists carbachol, oxotremorine, and pilocarpine 10-min exposure to xanomeline did not cause internalization of any receptor subtype. 3/Wash-resistant xanomeline selectively prevented further increase in intracellular calcium by carbachol at hM 1  and hM 4  receptors. 4/After transient activation xanomeline behaved as a long-term antagonist at hM 5  receptors. 5/The antagonist N-methylscopolamine (NMS) reversibly blocked activation of hM 1  through hM 4  receptors by xanomeline. 6/NMS prevented formation of xanomeline wash-resistant binding and activation at hM 2  and hM 4  receptors and slowed them at hM 1 , hM 3  and hM 5  receptors. Our results show commonalities of xanomeline reversible and wash-resistant binding and short-time activation among the five muscarinic receptor subtypes. However long-term receptor activation takes place in full only at hM 1  and hM 4  receptors. Moreover xanomeline displays higher efficacy at hM 1  and hM 4  receptors in primary phasic intracellular calcium release. These findings suggest the existence of particular activation mechanisms specific to these two receptors.

Long-Term Activation upon Brief Exposure to Xanomleline Is Unique to M1 and M4 Subtypes of Muscarinic Acetylcholine Receptors