The muscarinic acetylcholine receptor M2, also known as the cholinergic receptor, muscarinic 2, is a muscarinic acetylcholine receptor that in humans is encoded by the CHRM2gene. Multiple alternatively spliced transcript variants have been described for this gene.
The M2 muscarinic receptors are located in the heart, where they act to slow the heart rate down to normal sinus rhythm after positive stimulatory actions of the parasympathetic nervous system, by slowing the speed of depolarization. They also reduce contractile forces of the atrial cardiac muscle, and reduce conduction velocity of the atrioventricular node (AV node). However, they have little effect on the contractile forces of the ventricular muscle, slightly decreasing force.
A Dutch family study found that there is "a highly significant association" between the CHRM2gene and intelligence as measured by the Wechsler Adult Intelligence Scale-Revised. A similar association was found independently in the Minnesota Twin and Family Study.
However, a larger 2009 study attempting to replicate this claim instead found no significant association between the CHRM2 gene and intelligence.
M2 muscarinic receptors act via a Gi type receptor, which causes a decrease in cAMP in the cell, generally leading to inhibitory-type effects. They appear to serve as autoreceptors.
In addition, they modulate muscarinic potassium channels. In the heart, this contributes to a decreased heart rate. They do so by the Gβγ subunit of the G protein; Gβγ opens K+ channels in the parasympathetic notches in the heart, which causes an outward current of potassium, which slows down the heart rate.
Few highly selective M2 agonists are available at present, although there are several non-selective muscarinic agonists that stimulate M2, and a number of selective M2 antagonists are available.
(2S,2'R,3'S,5'R)-1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine 3-sulfoxide methyl iodide (selective for M2 but only partial agonist)
↑Gosso MF, van Belzen M, de Geus EJ, Polderman JC, Heutink P, Boomsma DI, Posthuma D (November 2006). "Association between the CHRM2 gene and intelligence in a sample of 304 Dutch families". Genes, Brain, and Behavior. 5 (8): 577–84. doi:10.1111/j.1601-183X.2006.00211.x. PMID17081262.
↑Comings DE, Wu S, Rostamkhani M, McGue M, Lacono WG, Cheng LS, MacMurray JP (January 2003). "Role of the cholinergic muscarinic 2 receptor (CHRM2) gene in cognition". Molecular Psychiatry. 8 (1): 10–1. doi:10.1038/sj.mp.4001095. PMID12556901.
↑Dick DM, Aliev F, Kramer J, Wang JC, Hinrichs A, Bertelsen S, Kuperman S, Schuckit M, Nurnberger J, Edenberg HJ, Porjesz B, Begleiter H, Hesselbrock V, Goate A, Bierut L (March 2007). "Association of CHRM2 with IQ: converging evidence for a gene influencing intelligence". Behavior Genetics. 37 (2): 265–72. doi:10.1007/s10519-006-9131-2. PMID17160701.
↑Lind PA, Luciano M, Horan MA, Marioni RE, Wright MJ, Bates TC, Rabbitt P, Harris SE, Davidson Y, Deary IJ, Gibbons L, Pickles A, Ollier W, Pendleton N, Price JF, Payton A, Martin NG (September 2009). "No association between Cholinergic Muscarinic Receptor 2 (CHRM2) genetic variation and cognitive abilities in three independent samples". Behavior Genetics. 39 (5): 513–23. doi:10.1007/s10519-009-9274-z. PMID19418213.
↑Douglas CL, Baghdoyan HA, Lydic R (December 2001). "M2 muscarinic autoreceptors modulate acetylcholine release in prefrontal cortex of C57BL/6J mouse". The Journal of Pharmacology and Experimental Therapeutics. 299 (3): 960–6. PMID11714883.
↑Melchiorre C, Angeli P, Lambrecht G, Mutschler E, Picchio MT, Wess J (December 1987). "Antimuscarinic action of methoctramine, a new cardioselective M-2 muscarinic receptor antagonist, alone and in combination with atropine and gallamine". European Journal of Pharmacology. 144 (2): 117–24. doi:10.1016/0014-2999(87)90509-7. PMID3436364.
Brann MR, Ellis J, Jørgensen H, Hill-Eubanks D, Jones SV (1994). "Muscarinic acetylcholine receptor subtypes: localization and structure/function". Progress in Brain Research. 98: 121–7. doi:10.1016/S0079-6123(08)62388-2. PMID8248499.
van Koppen CJ, Nathanson NM (December 1990). "Site-directed mutagenesis of the m2 muscarinic acetylcholine receptor. Analysis of the role of N-glycosylation in receptor expression and function". The Journal of Biological Chemistry. 265 (34): 20887–92. PMID2249995.
Ashkenazi A, Ramachandran J, Capon DJ (July 1989). "Acetylcholine analogue stimulates DNA synthesis in brain-derived cells via specific muscarinic receptor subtypes". Nature. 340 (6229): 146–50. doi:10.1038/340146a0. PMID2739737.
Bonner TI, Buckley NJ, Young AC, Brann MR (July 1987). "Identification of a family of muscarinic acetylcholine receptor genes". Science. 237 (4814): 527–32. doi:10.1126/science.3037705. PMID3037705.
Badner JA, Yoon SW, Turner G, Bonner TI, Detera-Wadleigh SD (July 1995). "Multipoint genetic linkage analysis of the m2 human muscarinic receptor gene". Mammalian Genome. 6 (7): 489–90. doi:10.1007/BF00360666. PMID7579899.
Offermanns S, Simon MI (June 1995). "G alpha 15 and G alpha 16 couple a wide variety of receptors to phospholipase C". The Journal of Biological Chemistry. 270 (25): 15175–80. doi:10.1074/jbc.270.25.15175. PMID7797501.
Kunapuli P, Onorato JJ, Hosey MM, Benovic JL (January 1994). "Expression, purification, and characterization of the G protein-coupled receptor kinase GRK5". The Journal of Biological Chemistry. 269 (2): 1099–105. PMID8288567.
Haga K, Kameyama K, Haga T, Kikkawa U, Shiozaki K, Uchiyama H (February 1996). "Phosphorylation of human m1 muscarinic acetylcholine receptors by G protein-coupled receptor kinase 2 and protein kinase C". The Journal of Biological Chemistry. 271 (5): 2776–82. doi:10.1074/jbc.271.5.2776. PMID8576254.
Kostenis E, Conklin BR, Wess J (February 1997). "Molecular basis of receptor/G protein coupling selectivity studied by coexpression of wild type and mutant m2 muscarinic receptors with mutant G alpha(q) subunits". Biochemistry. 36 (6): 1487–95. doi:10.1021/bi962554d. PMID9063897.
Smiley JF, Levey AI, Mesulam MM (June 1998). "Infracortical interstitial cells concurrently expressing m2-muscarinic receptors, acetylcholinesterase and nicotinamide adenine dinucleotide phosphate-diaphorase in the human and monkey cerebral cortex". Neuroscience. 84 (3): 755–69. doi:10.1016/S0306-4522(97)00524-1. PMID9579781.
von der Kammer H, Mayhaus M, Albrecht C, Enderich J, Wegner M, Nitsch RM (June 1998). "Muscarinic acetylcholine receptors activate expression of the EGR gene family of transcription factors". The Journal of Biological Chemistry. 273 (23): 14538–44. doi:10.1074/jbc.273.23.14538. PMID9603968.
Sato KZ, Fujii T, Watanabe Y, Yamada S, Ando T, Kazuko F, Kawashima K (April 1999). "Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukocytes and leukemic cell lines". Neuroscience Letters. 266 (1): 17–20. doi:10.1016/S0304-3940(99)00259-1. PMID10336173.
Retondaro FC, Dos Santos Costa PC, Pedrosa RC, Kurtenbach E (November 1999). "Presence of antibodies against the third intracellular loop of the m2 muscarinic receptor in the sera of chronic chagasic patients". FASEB Journal. 13 (14): 2015–20. PMID10544184.
Waid DK, Chell M, El-Fakahany EE (July 2000). "M(2) and M(4) muscarinic receptor subtypes couple to activation of endothelial nitric oxide synthase". Pharmacology. 61 (1): 37–42. doi:10.1159/000028378. PMID10895079.
Obara K, Arai K, Miyajima N, Hatano A, Tomita Y, Takahashi K (June 2000). "Expression of m2 muscarinic acetylcholine receptor mRNA in primary culture of human prostate stromal cells". Urological Research. 28 (3): 196–200. doi:10.1007/s002400000113. PMID10929429.
Matera C, Flammini L, Quadri M, Vivo V, Ballabeni V, Holzgrabe U, Mohr K, De Amici M, Barocelli E, Bertoni S, Dallanoce C (March 2014). "Bis(ammonio)alkane-type agonists of muscarinic acetylcholine receptors: synthesis, in vitro functional characterization, and in vivo evaluation of their analgesic activity". European Journal of Medicinal Chemistry. 75: 222–32. doi:10.1016/j.ejmech.2014.01.032. PMID24534538.