Disease relevance of Chrm2

• 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 [1].
• The muscarine-elicited depression of ACh release in normal junctions was completely abolished by pertussis toxin or methoctramine pretreatment, but was not affected by muscarinic toxin MT-3, thus indicating the involvement of the M2 mAChR [2].
• The role of the M5 mAChRs involves modulation of central dopamine function and the tone of cerebral blood vessels. mAChRs of the M2 subtype mediate muscarinic agonist-induced bradycardia, tremor, hypothermia, and autoinhibition of release in several brain regions [3].
• A CHO-K1 cell line transfected with the human m2 receptor was used as a homogeneous M2 tissue for comparison with two putative M4 systems (rat striatum and the N1E-115 mouse neuroblastoma cell line) [4].
• By whole-mount in situ hybridization, the M2 mAChR was first detectable in the heart, vagus motor ganglion, and vagus sensory ganglion at 30, 48 and 60 h.p.f., respectively [5].

Psychiatry related information on Chrm2

• These results support the interpretation that M2 receptors in the pontine reticular formation of B6 mouse contribute to the generation of REM sleep [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 Chrm2

• Channel gating governed symmetrically by conserved leucine residues in the M2 domain of nicotinic receptors [8].
• The cation-conducting channel of the nicotinic acetylcholine (ACh) receptor is lined by the first (M1) and second (M2) membrane-spanning segments of each of its five subunits [9].
• Six consecutive residues, alphaS239 to alphaT244, in the alpha subunit M1-M2 loop and at the intracellular end of M2 were mutated to cysteine [9].
• Identification of acetylcholine receptor channel-lining residues in the entire M2 segment of the alpha subunit [10].
• Each residue in and flanking the M2 membrane-spanning segment of the alpha subunit, from Glu-241 to Glu-262, was mutated to cysteine, and the mutant subunits were expressed together with wild-type beta, gamma, and delta subunits in Xenopus oocytes [10].

Chemical compound and disease context of Chrm2

• Loss of vagally mediated bradycardia and bronchoconstriction in mice lacking M2 or M3 muscarinic acetylcholine receptors [11].
• Here, we report that in vivo, bradycardia caused by vagal stimulation or administration of the muscarinic agonist methacholine (MCh) was abolished in mice lacking functional M2 mAChRs (M2-/- mice) [11].
• In conclusion, the results suggest that the M2 mAChR inhibit basal heart rate in zebrafish embryo and the M2 mAChR mediates the CCh-induced bradycardia [5].
• In pithed rats AF-DX 116 inhibits vagally-induced bradycardia, an M2 response, (ED50 32 micrograms/kg i.v.) in preference to the M1-mediated pressor response to McN-A-343 (ED50 211 micrograms/kg i.v.). AF-DX 116 further discriminates among M2 receptors, showing a high affinity for the cardiac muscarine receptors [12].
• Inhibition of cyclic AMP formation in N1E-115 neuroblastoma cells is mediated by a non-cardiac M2 muscarinic receptor subtype [13].

Biological context of Chrm2

• Chrm1, Chrm2, and Chrm3 were mapped to chromosome (Chr) 19, 6, and 13, respectively [14].
• These results demonstrate that cholinergic constriction of murine peripheral airways is mediated by the concerted action of the M2 and M3 receptor subtypes and suggest the existence of pulmonary M1 receptor activation, which counteracts cholinergic bronchoconstriction [15].
• The affinity of these compounds for muscarinic receptors was determined by inhibition of [3H]pirenzepine to M1 receptors in hippocampus, [3H]QNB to M2 receptors in brainstem, and [3H]oxotremorine-M to high affinity muscarinic agonist binding sites in cortex [16].
• Differential coupling of muscarinic M1, M2, and M3 receptors to phosphoinositide hydrolysis in urinary bladder and longitudinal muscle of the ileum of the mouse [17].
• Selective protection of muscarinic M2 receptors with methoctramine during 4-DAMP mustard alkylation of muscarinic M3 receptors provided no evidence for muscarinic M2 receptor-activated [Ca2+]i increase [18].

Anatomical context of Chrm2

• These results indicate that both M2 and M4 receptors mediate the muscarinic autoinhibition in ACh release in the LMMP preparation of the mouse ileum, and loss of one of these subtypes can be compensated functionally by a receptor that remained [19].
• Using ex vivo autoradiography, the regional brain localization of [(18)F]FP-TZTP in M2 knockout (M2 KO) was significantly decreased (51.3 to 61.4%; P<0.01) when compared to the wild-type (WT) mice in amygdala, brain stem, caudate putamen, cerebellum, cortex, hippocampus, hypothalamus, superior colliculus, and thalamus [20].
• M2 receptor immunoreactivity was located in both smooth muscle cells and enteric neurons [19].
• Using rat brain cortical membranes, SR 46559A was a competitive ligand (Ki = 112 nM) at muscarinic M1 receptors, its affinity for muscarinic M2 (cardiac) and M3 (glandular) receptors being 6-7 times lower [21].
• Our results show that the M1 and M2 mAChRs have opposite presynaptic functions in modulating quantal ACh release, and that regulation of release by the two receptor subtypes depends on the functional state of AChE at the neuromuscular junction [2].

Associations of Chrm2 with chemical compounds

• In M2 or M4 single-KO mice, oxotremorine-M produced a variable effect on sIPSCs; it increased the frequency of sIPSCs in some cells but decreased the sIPSC frequency in other neurons [22].
• We were surprised to find that in M2/M4 double-KO mice, oxotremorine-M consistently increased the frequency of sIPSCs and mIPSCs in all neurons tested, and this effect was completely abolished by 4-diphenylacetoxy-N-methylpiperidine methiodide, an M3 subtype-preferring antagonist [22].
• Roles of M2 and M4 muscarinic receptors in regulating acetylcholine release from myenteric neurons of mouse ileum [19].
• By contrast, an M2 receptor antagonist, methoctramine tetrahydrochloride (10 microM), was ineffective [23].
• Oxotremorine-induced tremor was abolished only in the M2 knockout mice [1].

Physical interactions of Chrm2

• In the present study, densities of the M1 and M2 subclasses of muscarinic cholinergic binding sites were assessed using quantitative receptor autoradiography in the brains of sparse-fur (spf) mice with congenital OTC deficiency and in age-matched CD-1 controls [24].

Enzymatic interactions of Chrm2

• This heteromolecular complex is coordinated by proline-rich and Src family-dependent phosphorylated regions of M2 [25].

Other interactions of Chrm2

• However, in the presence of the M2 and M4 subtype-preferring antagonist himbacine, oxotremorine-M caused a large increase in the sIPSC frequency [22].
• Further analyses employing pharmacological and genetic strategies demonstrate that TP-dependent changes in lung resistance and airway smooth muscle tension require expression of the M2 mAChR subtype [26].
• CHO M2 receptors mediated robust agonist-stimulated GTPgamma35S binding measured with anti-Galphai(1-3), but coupled only weakly to Galphaq/11 [27].
• M2 muscarinic receptors in pontine reticular formation of C57BL/6J mouse contribute to rapid eye movement sleep generation [6].
• Activation of Vav by the gammaherpesvirus M2 protein contributes to the establishment of viral latency in B lymphocytes [25].

Analytical, diagnostic and therapeutic context of Chrm2

• We found profound alterations in acetylcholine homeostasis in the hippocampus of both M2- and M4-KO mice as well as of the combined M2/M4-KOs, as assessed by in vivo microdialysis [28].
• To date, the mechanisms through which M2 autoreceptor antagonism causes cortical EEG activation have not been investigated [29].
• DNA immunizations with M2 muscarinic and beta1 adrenergic receptor coding plasmids impair cardiac function in mice [30].
• 3. Reverse transcription polymerase chain reaction and Southern blotting analysis demonstrated that the M2 mAChR mRNA levels increased during the segmentation period (12 h post-fertilization; h.p.f.) in zebrafish [5].
• Pharmacological and behavioral analysis of the resulting mutant mice showed that the M2 receptor subtype is critically involved in mediating three of the most striking central muscarinic effects, tremor, hypothermia, and analgesia [31].

References