Muscarinic GPCR Family Subtypes and Products

What Are Muscarinic Receptors?

Muscarinic acetylcholine receptors are a family of G protein-coupled receptors (GPCRs) comprised of five receptor subtypes: M1, M2, M3, M4, and M5. Muscarinic receptors are a major drug target for various human diseases, and plays a large role in a variety of physiological responses. There is therapeutic potential for many muscarinic agonists and antagonists. For example, M1 agonists have therapeutic potential in the treatment of Alzheimer’s, Sjogren’s, and Schizophrenia, while M1 antagonists have potential in treating Parkinson’s. M3 agonists also have potential in the treatment of Type II diabetes, while antagonists have application in treating obesity, peptic ulcers, and IBS.

Muscarinic Receptor Information

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The muscarinic M1 receptor is a membrane protein with seven transmembrane segments and binds with acetylcholine on the extracellular surface. The acetylcholine-bound receptor interacts with and activates G protein Gq/G11. The receptor is found in the hippocampal and cortical regions of the brain as well as in the parasympathetic ganglia. It is involved in many processes, including the initiation of seizures, learning and memory, and regulation of the force and rate of heart contractions. Because of its involvement in these processes, the M1 receptor is a compelling drug target for Alzheimer’s disease and other neurological and psychiatric disorders.

The muscarinic M2 receptor is a 466-amino acid, 7-transmembrane protein. In heart muscle, M2 receptors represent the prevailing subtype of muscarinic receptors. They can also be found in neurons of central and peripheral nervous system. In neuronal cells, mainly on synaptic terminals, stimulation of the M2 autoreceptors is responsible for presynaptic muscarinic autoinhibition of acetylcholine release in both central and peripheral cholinergic neurons. Loss of function of these M2 receptors, as occurs in some patients with asthma and in animal models of inflammation, leads to an increase in vagally mediated hyperreactivity.

The muscarinic M3 receptor is a 590-amino acid, 7-transmembrane protein. RT-PCR and radioligand binding assays detected M3 expression in the bladder, gastric and intestinal smooth muscle, brain (CNS) and the vestibular system. Muscarinic M3 receptors mediate contraction of airway and bladder smooth muscles. The receptors in the urothelium/suburothelium can also modulate the release of certain factors, which in turn may affect bladder function at the efferent or afferent axis. Blockade of M3 receptors can alleviate the symptoms of OAB. M3 receptors are also expressed myocardial tissues and are of potential roles in parasympathetic control of heart function under normal physiological conditions and in heart failure, myocardial ischemia and arrhythmias.

The human muscarinic M4 receptor is a 479-amino acid, 7- transmembrane protein. In heart muscle, M4 receptors are coupled to specific K+ currents that regulate cardiac muscle contractions. They can also be found in tissues of the central nervous system and bladder.

The muscarinic M5 receptor is a 532-amino acid 7-transmembrane protein. Acetylcholine, a potent dilator of most vascular beds, virtually lost the ability to dilate cerebral arteries and arterioles in M5 -/- mice, suggesting that endothelial M5 receptors mediate this activity in wild-type mice. M5 receptors located on dopaminergic nerve terminals play a role in facilitating muscarinic agonist-induced dopamine release in the striatum. Both somatic and affective components of naloxone-induced morphine withdrawal symptoms were significantly attenuated in M5 -/- mice. M5 receptor activity modulates both morphine reward and withdrawal processes, suggesting that M5 receptors may represent a novel target for the treatment of opiate addiction.

Muscarinic Cell Lines

Receptor FamilyReceptorSpeciesParentalStable Cell Lines Division-Arrested Cells Membranes
M4humanCHO-K1 Gαqi5CG1025-1DCG1025-1MCG1025-1