Muscarinic acetylcholine receptor M2

Function

Heart

The M2 muscarinic receptors are located in the heart, where they act to slow the heart rate down to normal sinus rhythm after negative 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.

Airway smooth muscle

Both M2 and M3 muscarinic receptors are expressed in the smooth muscles of the airway, with the majority of the receptors being the M2 type. Activation of the M2 receptors, which are coupled to Gi, inhibits the β-adrenergic mediated relaxation of the airway smooth muscle. Synergistically, activation of the M3 receptors, which couple to Gq, stimulates contraction of the airway smooth muscle.

IQ

A Dutch family study found that there is "a highly significant association" between the CHRM2 gene 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.

Olfactory behavior

Mediating olfactory guided behaviors (e.g. odor discrimination, aggression, mating).

Mechanism of action

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 generally serve as autoreceptors.

In addition, they modulate G protein-coupled inwardly-rectifying potassium channels. In the heart, this contributes to a decreased heart rate. They do so by the Gβγ subunit of the G protein; Gβγ shifts the open probability of K+ channels in the membrane of the cardiac pacemaker cells, which causes an outward current of potassium, effectively hyperpolarizing the membrane, which slows down the heart rate.

Ligands

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.

Agonists

• (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)
• Berberine
• Iper-8-Naph (alias N-8-Iper, bitopic/dualsteric agonist)
• Methacholine
• PAI (photoswitchable agonist)

Positive allosteric modulators

• BAY 2413555

Antagonists

• AFDX-384
• Atropine
• Chlorpromazine
• Dicycloverine
• Dimenhydrinate
• Dimethindene
• Diphenhydramine
• Gallamine
• Hyoscyamine
• Ipratropium
• Methoctramine
• Otenzepad
• Oxybutynin
• Tolterodine
• Trimipramine

References

References

1. "Entrez Gene: CHRM2 cholinergic receptor, muscarinic 2".
2. (January 1999). "Role of M2 muscarinic receptors in airway smooth muscle contraction". Life Sciences.
3. (November 2006). "Association between the CHRM2 gene and intelligence in a sample of 304 Dutch families". Genes, Brain and Behavior.
4. (January 2003). "Role of the cholinergic muscarinic 2 receptor (CHRM2) gene in cognition". Molecular Psychiatry.
5. (March 2007). "Association of CHRM2 with IQ: converging evidence for a gene influencing intelligence". Behavior Genetics.
6. (September 2009). "No association between Cholinergic Muscarinic Receptor 2 (CHRM2) genetic variation and cognitive abilities in three independent samples". Behavior Genetics.
7. (July 2015). "Differential Muscarinic Modulation in the Olfactory Bulb". The Journal of Neuroscience.
8. (December 2001). "M2 muscarinic autoreceptors modulate acetylcholine release in prefrontal cortex of C57BL/6J mouse". The Journal of Pharmacology and Experimental Therapeutics.
9. (2003). "Pharmacology". Churchill Livingstone.
10. (2005). "Medical Physiology". Elsevier Saunders.
11. (March 2006). "Highly chiral muscarinic ligands: the discovery of (2S,2'R,3'S,5'R)-1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine 3-sulfoxide methyl iodide, a potent, functionally selective, M2 partial agonist". Journal of Medicinal Chemistry.
12. (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.
13. (September 2018). "Activation of M2 muscarinic acetylcholine receptors by a hybrid agonist enhances cytotoxic effects in GB7 glioblastoma cancer stem cells". Neurochemistry International.
14. (2012-09-04). "The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling". Nature Communications.
15. (May 2019). "Optical Control of Cardiac Function with a Photoswitchable Muscarinic Agonist". Journal of the American Chemical Society.
16. (May 2010). "ED-SPAZ- hyoscyamine sulfate tablet, orally disintegrating". U.S. National Library of Medicine.
17. (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.