期刊
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
卷 327, 期 2, 页码 365-374出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.108.141788
关键词
-
资金
- Biotechnology and Biological Sciences Research Council/GlaxoSmithKline
The M-1 muscarinic acetylcholine (mACh) receptor is among a growing number of G protein-coupled receptors that are able to activate multiple signaling cascades. AC-42 (4-n-butyl-1-[4-(2methylphenyl)-4-oxo-1-butyl] piperidine) is an allosteric agonist that can selectively activate the M 1 mACh receptor in the absence of an orthosteric ligand. Allosteric agonists have the potential to stabilize unique receptor conformations, which may in turn cause differential activation of signal transduction pathways. In the present study, we have investigated the signaling pathways activated by AC-42, its analog 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl) propyl]-3,4-dihydro-2(1H)-quinolinone), and a range of orthosteric muscarinic agonists [oxotremorine- M (oxo-M), arecoline, and pilocarpine] in Chinese hamster ovary cells recombinantly expressing the human M 1 mACh receptor. Each agonist was able to activate G alpha(q/11)-dependent signaling, as demonstrated by an increase in guanosine 5'-O-(3- thiotriphosphate) ([S-35]GTP gamma S) binding to G alpha(q/11) proteins and total [H-3] inositol phosphate accumulation assays in intact cells. All three orthosteric agonists caused significant enhancements in [S-35] GTP gamma S binding to G alpha(i1/2) subunits over basal; however, neither allosteric ligand produced a significant response. In contrast, both orthosteric and allosteric agonists are able to couple to the G alpha(s)/cAMP pathway, enhancing forskolin-stimulated cAMP accumulation. These data provide support for the concept that allosteric and orthosteric mACh receptor agonists both stabilize receptor conformations associated with G alpha(q/11) and G alpha(s)-dependent signaling; however, AC-42 and 77-LH28-1, unlike oxo-M, arecoline, and pilocarpine, do not seem to promote M-1 mACh receptor- G alpha(i1/2) coupling, suggesting that allosteric agonists have the potential to activate distinct subsets of downstream effectors.
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