Free shipping starts now, no minimum, no coupons required!

Muscarinic Receptors

Acetylcholine, the major neurotransmitter in the central and the peripheral nervous system, can act through two kinds of receptors1: ionotropic and metabotropic. The ionotropic are rapidly activated ion channels2. The metabotropic receptors regulate ion channels and other physiological processes through binding to and activation of the G protein. The cetylcholine metabotropic receptors are also called muscarinic receptors (mAChR).

mAChR are widely distributed through the body and found among various mammalian species3. Like other G-protein coupled receptors, they have seven transmembrane domains with extracellular N-terminus. Acetylcholine is supposed to bind to a pocket surrounded by six transmembrane segments and the coupling to G protein occurs at the third loop on the cytoplasmatic side of the receptor4. Today, five subtypes of the muscarinic receptors have been cloned. They differ in their distributions and their affinities to agonists and antagonists. Although all of them are found in the brain, m1 and m3 are also present in exocrine glands5. Both can activate signaling effectors: Phospholipase A2, C, D, Tyrosine Kinase and a voltage insensitive Ca2+channel. m2, found in heart, is coupled to and mediates the slowing of heart rate in response to acetylcholine. This inhibitory effect is also found in the case of m4 which is present in lung and neural tissues.

Muscarinic receptors are the target of various toxins: Mamba snake venom and pertussis toxin (PTX) are some examples6. PTX can bind all of the 5 subtypes and cause modulation of the ion channel through sensitive G protein (in the case of m2 and m4) or insensitive G protein (m1, m3 and m5 receptors)7, 8. Pharmacological effect of agonists or antagonists on mAChR have already been shown. An agonist to m1 has been found to reduce amyloid precursor protein coupling which occurs in Alzheimer’s disease9. Use of an m4 selective antagonist has been used in Parkinson’s disease to reduce release of dopamine10.

References

  1. Dale, H. (1914) J. Pharmac. Exp. Ther., 6, 14.
  2. Stroud, R. M. et. al. (1985) Annu. Rev. Cell. Biol. 1, 317.
  3. Wess, J. (1993) Life Sci. 53, 1447.
  4. Hulme, E. et. al. (1991) Biochem. Soc. Trans. 19, 133.
  5. Hulme, E. et. al. (1990) Ann. Rev. Pharmac. Toxicol. 30, 633.
  6. Jerusalinsky, D. et. al. (1992) Neurochem. Int., 20, 237.
  7. Peralta, E.G. et. al. (1987) Nature 334, 434.
  8. Caufield, M.D. (1993) Pharmacol. Ther. 58, 319.
  9. Fisher, A. et. al. (1996) Ann N Y Acad. Sci, 777, 189.
  10. Rang, H.P. and Dale, M.M. (1991) Pharmacology Edinburgh, London, Melbourne, New York, Tokyo and Madrid: Churchill Livingstone.