M4 Muscarinic Acetylcholine Receptor Antibodies

The M4 muscarinic acetylcholine receptor, encoded by the CHRM4 gene, is predominantly expressed in the striatum, cortex, and hippocampus, where it plays an important role in regulating motor function, cognition, and dopaminergic neurotransmission. M4 primarily couples to Gi/o proteins, leading to inhibition of adenylyl cyclase, reduced cAMP production, and modulation of ion channel activity. Through these mechanisms, M4 suppresses neuronal excitability and neurotransmitter release. M4 expression is regulated by developmental processes, neuronal activity, and receptor trafficking pathways that include phosphorylation, desensitization, and internalization. Dysregulation of M4 signaling has been implicated in schizophrenia, Parkinson’s disease, and substance use disorders. The therapeutic potential of M4 has led to the development of selective agonists and positive allosteric modulators. Xanomeline, which preferentially activates M1 and M4, has demonstrated clinical efficacy and was recently approved in combination with trospium for the treatment of schizophrenia. In addition, highly selective M4-targeted compounds remain under active clinical and preclinical investigation for neuropsychiatric disorders. Functionally, M4-muscarinic receptors are able to couple to the pertusiss toxin-sensitive Gi/o proteins. M4-muscarinic receptor knockout animals show locomotor phenotypes. In fact, M4 receptors are thought to mediate an inhibitory affect on striatal dopamine-mediated locomotor activity. M4 agonists might be beneficial in schizophrenia and antagonists are likely to be of benefit in Parkinson's disease. M4 receptor activity is regulated by phosphorylation of serine296/serine297 and threonine311/serine314 in the 3rd intracellular loop. This nomenclature refers to the human M4 but is highly conserved in mice and rats. For more information on M4 receptor pharmacology please refer to the IUPHAR database. For further reading refer to:

Caulfield MP, Birdsall NJ. International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev. 1998 Jun;50(2):279-90. PMID: 9647869.

Wess J, Eglen RM, Gautam D. Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development. Nat Rev Drug Discov. 2007 Sep;6(9):721-33. doi: 10.1038/nrd2379. PMID: 17762886.

Birdsall NJM, Bradley S, Brown DA, Buckley NJ, Challiss RJ, Christopoulos A, Eglen RM, Ehlert F, Felder CC, Hammer R, Kilbinger HJ, Lambrecht G, Langmead C, Mitchelson F, Mutschler E, Nathanson NM, Schwarz RD, Thal D, Tobin AB, Valant C, Wess J. Acetylcholine receptors (muscarinic) in GtoPdb v.2021.3. IUPHAR/BPS Guide to Pharmacology CITE. 2021; 2021(3).