Long-term Wash-resistant Effects of Brief Interaction of Xanomeline at the M1 Muscarinic Receptor.
From: Division of Neuroscience Research in Psychiatry, University of Minnesota Medical School, Mayo Mail Code 392, 420 Delaware St. SE, Minneapolis, MN 55455, USA.
Neuroscience letters
- Publish Date: Dec 2006
- ISSN: 0304-3940
- Volume: 410
- Issue: 1
- Pages: 11-4
- Medium: Print
- Language: English
- Citation (JAMA): De Lorme Kayla C, Sikorski Krista L, Grant Marianne K O, et al. Long-term Wash-resistant Effects of Brief Interaction of Xanomeline at the M1 Muscarinic Receptor.. Neurosci. Lett. Dec 2006;410:11-4
Abstract
Compared to other M(1) muscarinic acetylcholine receptor (M(1) mAChR) agonists, xanomeline demonstrates both reversible and persistent modes of binding to the receptor. In our study, we investigated the long-term consequences of brief incubation of Chinese hamster ovary cells expressing M(1) mAChR (M(1)-CHO) with low concentrations of xanomeline followed by washing off the free drug. Thus, M(1)-CHO cells were exposed to 100 nM xanomeline for 1h then washed extensively. Washed cells were either used immediately for binding assays or incubated for 23 h in the absence of free xanomeline. Only the latter treatment conditions resulted in marked attenuation of binding of the muscarinic radioligand [(3)H]N-methylscopolamine ([(3)H]NMS) to intact cells. Shortening the xanomeline pretreatment period to 1 min had the same trends as the 1h pretreatment, implying that xanomeline binds instantly to the receptor to elicit long-term wash-resistant effects. Presence of atropine during the brief period of xanomeline pretreatment did not markedly modulate xanomeline’s long-term effects, which suggests that persistent anchoring of the xanomeline molecule to the M(1) receptor takes place at a site distinct from the orthosteric binding domain. Our findings suggest the possibility of a time-dependent transition of the conformation of the muscarinic M(1) receptor-xanomeline complex between states that vary in their ability to bind [(3)H]NMS. However, possible involvement of other mechanisms of long-term receptor regulation cannot be discounted.
Mesh Headings (Keywords): Animals, Atropine, Binding, Competitive, CHO Cells, Cricetinae, Cricetulus, Drug Interactions, Humans, Muscarinic Agonists, Muscarinic Antagonists, N-Methylscopolamine, Pyridines, Receptor, Muscarinic M1, Thiadiazoles, Time Factors, Transfection, Tritium
Check for Full Text / PubMed Unique Identifier (PMID): 17052840
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