Disease relevance of Chrm1

• Pertussis toxin (PTX) treatment of CHO M1 cells before membrane preparation resulted in a marked reduction in agonist-stimulated GTPgamma35S binding to whole membranes [1].
• In addition, the mechanical hypersensitivity in diabetic mice was reduced by the selective muscarinic M1 receptor agonist McN-A-343 (4-(m-chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium chloride) (i.t.). These results suggest that spinal muscarinic M1 receptors participate in the antiallodynic effect of clonidine in diabetic mice [2].
• The effect of chronic membrane depolarization on the regulation of muscarinic acetylcholine receptor (mAChR) number was studied in neuroblastoma cells (clone N1E-115) [3].
• Novel fragments of the Sjögren's syndrome autoantigens alpha-fodrin and type 3 muscarinic acetylcholine receptor generated during cytotoxic lymphocyte granule-induced cell death [4].
• In studies reported here, we compared the expression of the genes that code for the M1 and M2 subunits of ribonucleotide reductase in S49 cells, which are arrested in G1 phase by agents that increase cyclic AMP, with those from CEM human T lymphoma cells that are unaffected by exposure to dibutyryl cyclic AMP [5].

Psychiatry related information on Chrm1

• We report that M1 deficiency leads to elevated dopaminergic transmission in the striatum and significantly increased locomotor activity [6].
• In the present study, we examined whether the memory deficits and brain cholinergic deficiency of apoE-deficient mice can be ameliorated by the M1-selective agonist 1-methylpiperidine-4-spiro-(2'-methylthiazoline), [AF150(S)] [7].
• The data show that the selective M1 agonist AF102B can restore AF64A-induced cognitive impairments, without producing adverse central and peripheral side effects at the effective doses and this can indicate its potential use for the treatment of Alzheimer's disease [8].
• 2,8-Dimethyl-1-oxa-8-azaspiro[4,5]decan-3-one (17), designed by incorporating the tetrahydrofuran ring moiety of muscarone into an 8-azaspiro[4,5]decane skeleton, and related 1-oxa-8-azaspiro[4.5]decanes were synthesized and assessed as M1 muscarinic agonists for the symptomatic treatment of dementia of Alzheimer's type [9].
• Although the data show that central nicotinic and muscarinic antagonists both modulate working memory performance, they indicate first, that scopolamine-induced "amnesia" results, not from selective post-synaptic M1 muscarinic blockade but from indirect over-activation of nicotinic receptors [10].

High impact information on Chrm1

• Antipsychotics block muscarinic acetylcholine receptor-mediated cyclic GMP formation in cultured mouse neuroblastoma cells [11].
• Muscarinic acetylcholine receptor knockout mice: novel phenotypes and clinical implications [12].
• Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice [13].
• Here we examined memory in mice with a null mutation of the gene coding the M1 receptor, the most densely distributed muscarinic receptor in the hippocampus and forebrain [13].
• The identical motif was found on the M1 matrix protein of influenza B viruses, and affinity-purified human anti-ERKRR autoantibodies recognized this epitope also in the viral amino acid sequence context [14].

Chemical compound and disease context of Chrm1

• The muscarine-induced increase of ACh release in AChE-deficient junctions was not affected by pertussis toxin, but was completely blocked by MT-7, a specific M1 mAChR antagonist [15].
• Dendritic cells presenting pyruvate kinase M1/M2 isozyme peptide can induce experimental allergic myositis in BALB/c mice [16].
• Prediction of drug-induced catalepsy based on dopamine D1, D2, and muscarinic acetylcholine receptor occupancies [17].
• Activation of the phosphoinositide pathway by a transfected M1 muscarinic acetylcholine receptor expressed in WEHI-231 B lymphoma cells did not increase the amount of PtdIns 3-kinase activity which could be precipitated with anti-Tyr(P) antibodies [18].
• One of these putative unique genes, the M1 open reading frame (ORF), exhibits sequence homology to a poxvirus serine protease inhibitor, SPI-1, as well as to another gammaHV68 gene, M3, which we have recently shown encodes an abundantly secreted chemokine binding protein [19].

Biological context of Chrm1

• However, the contribution of individual muscarinic acetylcholine receptor subtypes to the constriction of smaller intrapulmonary airways that are primarily responsible for airway resistance has not been analyzed [20].
• 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 [20].
• 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 [21].
• Pilocarpine-induced increases in in vivo phosphoinositide hydrolysis were completely absent in hippocampus and cortex of M1 knockout mice, but in vivo phosphoinositide hydrolysis was unaltered in the M2-M5 knockout mice [22].
• 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 [23].

Anatomical context of Chrm1

• Quantitative reverse transcriptase-polymerase chain reaction studies with salivary gland tissue showed that the inactivation of the M(1) or M(3) mAChR genes did not lead to significantly altered mRNA levels of the remaining mAChR subtypes [24].
• Direct coupling of M1 receptors in CHO cells to inhibitory G proteins was demonstrated using an anti-Galphai(1-3) antibody, and this binding was inhibited by 76% following PTX treatment [1].
• 3-Cl-propylthio-TZTP and propoxy-TZTP had virtually no effect at the M1 receptor subtype as measured by the human m1 clone expressed in baby hamster kidney cells or the rabbit vas deferens assay [25].
• Maximal carbachol-induced secretion from M1R-/- mouse gastric glands was decreased by 25% [26].
• Cholinergic agonist-induced pepsinogen secretion from murine gastric chief cells is mediated by M1 and M3 muscarinic receptors [26].

Associations of Chrm1 with chemical compounds

• 2. Atropine, 4-diphenylacetoxy-N-methylpiperidine (4-DAMP, a muscarinic M3 antagonist), pirenzepine (a muscarinic M1 antagonist), methoctramine and gallamine (muscarinic M2 antagonists) inhibited the acetylcholine-induced Ca2+ release, with a high affinity for 4-DAMP and atropine and a low affinity for the other antagonists [27].
• A high dose of pilocarpine (300 mg/kg) caused seizures and lethality in wild-type and M2-M5 knockout mice, but produced neither effect in the M1 knockout mice [22].
• 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) [23].
• These compounds, however, were more potent in the analgesia tests than the selective M1 agonists xanomeline and hexylthio-TZTP [25].
• The clonidine-induced increase in mechanical threshold was inhibited by i.t. injection of the M1 receptor antagonist pirenzepine in a dose-dependent manner, and by the M3 receptor antagonist 4-DAMP, but not by the M2 receptor antagonist methoctramine [28].

Physical interactions of Chrm1

• Atropine and microinjected GDP beta S block the acetylcholine-induced ZP2 conversion, suggesting that the acetylcholine effects are mediated via a functional G protein-coupled m1 receptor [29].

Regulatory relationships of Chrm1

• M1 receptor activation by carbachol in TMps triggers neovascularization through arginase products because Nomega-hydroxy-L-arginine reversed the agonist action [30].
• The stimulation of phosphatidylinositol metabolism mediated by the M1 receptor was not altered by prior treatment of Y1 cells with concentrations of islet-activating protein sufficient to eliminate M2 receptor-mediated inhibition of adenylate cyclase [31].
• M1 muscarinic acetylcholine receptors activate extracellular signal-regulated kinase in CA1 pyramidal neurons in mouse hippocampal slices [32].
• Biochemical studies indicate that the M1 receptor plays a significant role in regulating G alpha q-mediated signal transduction in the hippocampus and cortex [33].
• GIRK1 expressed in Xenopus oocytes was activated by acetylcholine when m2 muscarinic acetylcholine receptor was coexpressed [34].

Other interactions of Chrm1

• Cholinergic stimulation of salivary secretion studied with M1 and M3 muscarinic receptor single- and double-knockout mice [24].
• In the M1-M4 KO mice, the number of [3H]NMS binding sites (Bmax) was decreased throughout the central nervous system (CNS) with significant regional differences [35].
• Regulation of muscarinic acetylcholine receptor function in acetylcholinesterase knockout mice [36].
• Veronal administration inhibited 50% BuChE activity in whole brain, cortex and hippocampus; concomitantly cortex mAChR was 30% reduced [37].
• Thus, dopamine receptors not only influence the cholinergic muscarinic receptors, but muscarinic M1 and M2 receptors also might mediate dopamine D1 and D2 receptor responses, respectively [38].

Analytical, diagnostic and therapeutic context of Chrm1

• 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 [26].
• The expression of mAchR, arginase and cyclo-oxygenase (COX) isoforms was analyzed by Western blotting [30].
• 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 [39].
• We have used gene targeting by homologous recombination in embryonic stem cells to produce mice lacking the m1 receptor [40].
• After a 6-h incubation, 10(-7) M PMA and 3 X 10(-7) M A23187 reduced mAChR number 30-40%, compared to the 40-50% reduction observed after treatment with 10(-3) M carbachol, a muscarinic agonist [41].

References