Disease relevance of Chrm3

• Here we show that mice deficient in the M3 muscarinic receptor (M3R-/- mice) display a significant decrease in food intake, reduced body weight and peripheral fat deposits, and very low levels of serum leptin and insulin [1].
• The muscarinic agonist oxotremorine induced marked hypothermia in all the knockout mice, but the hypothermia was reduced in M2 and to a lesser extent in M3 knockout mice [2].
• The M3 mAChRs are involved in exocrine gland secretion, smooth muscle contractility, pupil dilation, food intake, and weight gain [3].
• Loss of vagally mediated bradycardia and bronchoconstriction in mice lacking M2 or M3 muscarinic acetylcholine receptors [4].
• Furthermore, whereas all DSS-treated mice developed colitis, M3 KO mice displayed more rapid mass loss and more severe disease than DSS-treated WT mice, even following a reduction in the amount and time of DSS treatment [5].

Psychiatry related information on Chrm3

• Paradoxical sleep in mice lacking M3 and M2/M4 muscarinic receptors [6].
• Lu 25-109 [5-(2-ethyl-2H-tetrazol-5-yl)-1,2,3,6-tetrahydro-1-methylpyridine] , has M agonistic and M2/M3 antagonistic effects at muscarinic receptors in vitro; a pharmacological profile that may be beneficial in treatment of Alzheimer's disease [7].

High impact information on Chrm3

• However, M3R-/- mice remained responsive to the orexigenic effects of MCH [1].
• Our data indicate that there may be a cholinergic pathway that involves M3-receptor-mediated facilitation of food intake at a site downstream of the hypothalamic leptin/melanocortin system and upstream of the MCH system [1].
• Intra-cerebroventricular injection studies show that an agouti-related peptide analogue lacked orexigenic (appetite-stimulating) activity in M3R-/- mice [1].
• Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean [1].
• Paradoxically, hypothalamic messenger RNA levels of melanin-concentrating hormone (MCH), which are normally upregulated in fasted animals leading to an increase in food intake, are significantly reduced in M3R-/- mice [1].

Chemical compound and disease context of Chrm3

• M3 muscarinic receptor-deficient mice retain bethanechol-mediated intestinal ion transport and are more sensitive to colitis [5].
• Inactivation of Streptococcus pyogenes extracellular cysteine protease significantly decreases mouse lethality of serotype M3 and M49 strains [8].
• Muscarinic M3 receptors mediate total inositol phosphates accumulation in murine HSDM1C1 fibrosarcoma cells [9].

Biological context of Chrm3

• Chrm1, Chrm2, and Chrm3 were mapped to chromosome (Chr) 19, 6, and 13, respectively [10].
• These results suggest that the cholinergic inputs suppress GABAergic synaptic transmission to the SGI neurons at the presynaptic site via activation of M1 and, possibly, M3 receptors [11].
• The reduced hypotensive response of M3-/- mice to MCh suggests M3 mAChRs contribute to peripheral vasodilation [4].
• In contrast, heart rate responses remained unchanged in M3 receptor-deficient mice (M3-/- mice) [4].
• The relative contributions of M2 and M3 receptors in vitro was approximately 5 and 95% for the detrusor muscle contraction and approximately 25 and 75% for the ileal longitudinal muscle contraction, respectively [12].

Anatomical context of Chrm3

• Cholinergic agonist-induced pepsinogen secretion from murine gastric chief cells is mediated by M1 and M3 muscarinic receptors [13].
• In situ hybridization for murine M1R and M3R mRNA in gastric mucosa from WT mice revealed abundant signals for both receptor subtypes in the cytoplasm of chief cells [13].
• M1 and M3 receptors are localized to brain regions involved in cognition, such as hippocampus and cortex, but their relative contribution to function has been difficult to ascertain due to the lack of subtype specific ligands [14].
• M1, M3 and M5 receptors couple through G(alpha)(q) and function predominantly as postsynaptic receptors in the central nervous system [14].
• Mice lacking M2 and M3 muscarinic acetylcholine receptors are devoid of cholinergic smooth muscle contractions but still viable [12].

Associations of Chrm3 with chemical compounds

• The suppressant effect of muscarine was antagonized by an M1 receptor antagonist, pirenzepine dihydrochloride (1 microM), and a relatively specific M3 receptor antagonist, 4-DAMP methiodide (50 nM) [11].
• In contrast, there was only a slight decrease in carbachol potency and no change in efficacy when comparing M3R-/- with WT glands [13].
• Strikingly, oxotremorine-mediated potentiation of stimulated striatal [3H]dopamine release was abolished in M4 receptor KO mice, significantly increased in M3 receptor-deficient mice, and significantly reduced (but not abolished) in M5 receptor KO mice [15].
• This response was completely blocked by preincubating TMps with pirenzepine and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP), M1 and M3 receptor antagonists, and partly by the M2 receptor antagonist methoctramine [16].
• ACh and McN-A-343 produced endothelium-dependent dilation that was blocked by 4-diphenyl-N-methyl-piperidine methiodide, an inhibitor of the M3 receptor [17].

Physical interactions of Chrm3

• 6. Our results show that, in mouse duodenal myocytes, acetylcholine-induced release of Ca2+ from intracellular stores is mediated through activation of muscarinic M3 receptors which couple with a Gq protein to activate a phosphatidylinositol-specific phospholipase C [18].

Enzymatic interactions of Chrm3

• The study also demonstrates that M3R (which is restricted in expression to the peripheral autonomic organs) was efficiently cleaved by granzyme B (but not by caspases) at several sites, both in vitro and in intact cells [19].

Regulatory relationships of Chrm3

• KC migration and wound reepithelialization were facilitated by M4 and inhibited by M3 [20].

Other interactions of Chrm3

• Cholinergic stimulation of salivary secretion studied with M1 and M3 muscarinic receptor single- and double-knockout mice [21].
• Early in development, the M4 receptor is the predominant mAChR while the levels of the M2 and M3 receptors increase later in development [22].
• Specific Gq protein involvement in muscarinic M3 receptor-induced phosphatidylinositol hydrolysis and Ca2+ release in mouse duodenal myocytes [18].
• Additional in vitro studies showed that Oxo-M-mediated glucagon release was also virtually abolished in islets from M3(-/-) mice [23].
• OBJECTIVE: To determine whether the Sjögren's syndrome autoantigens alpha-fodrin and the type 3 muscarinic acetylcholine receptor (M3R) are cleaved during cytotoxic lymphocyte granule-induced death, to yield novel fragments [19].

Analytical, diagnostic and therapeutic context of Chrm3

• Thromboxane A2 induces airway constriction through an M3 muscarinic acetylcholine receptor-dependent mechanism [24].
• In rats, cholinergic functions mediated by M1 or M3 receptors (salivary secretion, pupil diameter, gastric emptying, intestinal transit time) were not affected by the oral administration of 8 even at doses as high as 30 times the antibradycardic effective dose [25].
• In the ileum, the M3 receptor may inhibit neuronally evoked ion transport, as indicated by the increased ISC responses to electrical stimulation in tissue from M3 KO mice [5].
• The m1 (%PI) SAR were distinctly different from the analgesia and the salivation SAR, suggesting that analgesia is mediated by neither m1 nor M3 muscarinic receptors [26].
• Quantitative RT-PCR revealed that the disruption of the M2R and M3R genes had no significant effect on the expression levels of the SPHK1-isoform in peripheral airways [27].

References