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CHRM4

Official Full Name
cholinergic receptor muscarinic 4
Organism
Homo sapiens
GeneID
1132
Background
The muscarinic cholinergic receptors belong to a larger family of G protein-coupled receptors. The functional diversity of these receptors is defined by the binding of acetylcholine and includes cellular responses such as adenylate cyclase inhibition, phosphoinositide degeneration, and potassium channel mediation. Muscarinic receptors influence many effects of acetylcholine in the central and peripheral nervous system. The clinical implications of this receptor are unknown; however, mouse studies link its function to adenylyl cyclase inhibition. [provided by RefSeq, Jul 2008]
Synonyms
HM4; M4R;
Bio Chemical Class
GPCR rhodopsin
Protein Sequence
MANFTPVNGSSGNQSVRLVTSSSHNRYETVEMVFIATVTGSLSLVTVVGNILVMLSIKVNRQLQTVNNYFLFSLACADLIIGAFSMNLYTVYIIKGYWPLGAVVCDLWLALDYVVSNASVMNLLIISFDRYFCVTKPLTYPARRTTKMAGLMIAAAWVLSFVLWAPAILFWQFVVGKRTVPDNQCFIQFLSNPAVTFGTAIAAFYLPVVIMTVLYIHISLASRSRVHKHRPEGPKEKKAKTLAFLKSPLMKQSVKKPPPGEAAREELRNGKLEEAPPPALPPPPRPVADKDTSNESSSGSATQNTKERPATELSTTEATTPAMPAPPLQPRALNPASRWSKIQIVTKQTGNECVTAIEIVPATPAGMRPAANVARKFASIARNQVRKKRQMAARERKVTRTIFAILLAFILTWTPYNVMVLVNTFCQSCIPDTVWSIGYWLCYVNSTINPACYALCNATFKKTFRHLLLCQYRNIGTAR
Open
Disease
Asthma, Attention deficit hyperactivity disorder, Eye anterior segment structural developmental anomaly, Glaucoma, Nausea/vomiting, Respiratory system disease
Approved Drug
4 +
Clinical Trial Drug
0
Discontinued Drug
0

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Detailed Information

Acetylcholine receptors, part of the G protein-coupled receptor (GPCR) family, help transmit signals inside cells by reacting with acetylcholine. Some of the reactions include blocking adenylate cyclase, breaking down phosphatidylinositol, and changing the activity of potassium ion channels. There are two main types of acetylcholine receptors: muscarinic (mAChRs) and nicotinic (nAChRs). They differ in how they work and where they are found in the body. Five subtypes—M1 to M5—are extra divisions for mAChRs; M1 and M4 subtypes are especially important in the central nervous system (CNS) for the control of brain processes.

Figure 1 describes how M1 and M4 muscarinic acetylcholine receptors modulate neurotransmission in the hippocampus to maintain cognitive function balance.Figure 1. M1 and M4 muscarinic receptors in the hippocampus modulate neurotransmission to maintain cognitive function balance. (Yohn SE, et al., 2024)

Functions and Distribution of the CHRM4 Gene

Widely expressed in sites including the striatum, caudate nucleus, and putamen of the brain, the M4 subtype of muscarinic acetylcholine receptors is encoded by the CHRM4 gene. Co-expressed with dopamine receptors, the M4 receptor controls dopamine release—a process vital for treating cognitive and behavioral abnormalities in neurodegenerative and neuropsychiatric disorders. Research shows that the M4 receptor is essential for effective, learning, and memory processes as well as for modulating neural excitability by suppressing adenylate cyclase.

The emergence of many neuropsychiatric diseases is intimately related to dysfunctional M4 receptors. Patients with schizophrenia, for example, typically show notable cognitive impairment, which is partially related to M4 receptor malfunction. The activation of M4 receptors may be inhibited in these individuals, therefore influencing normal neuronal transmission in regions such as the cerebral cortex and hippocampal area and aggravating cognitive impairment. As such, the M4 receptor has evolved as a possible target for reducing schizophrenic cognitive problems.

The Relationship Between M4 Receptor and Schizophrenia

A complicated and varied mental illness, schizophrenia is characterized by positive, negative, and cognitive symptoms among other things. With conventional antipsychotics, positive symptoms—such as hallucinations, delusions, and disordered thinking—can frequently be somewhat managed. Still, managing schizophrenia depends much on addressing cognitive symptoms, which present a great difficulty. Patients's everyday life and social functioning are much disrupted by cognitive deficiencies including lack of attention, poor memory, and decreased executive function.

Recent research suggests that cognitive symptoms of schizophrenia are caused in great part by the M4 receptor. By boosting neural signaling, activating the M4 receptor may help to increase cognitive ability. Especially in regions like the striatum and prefrontal cortex, the M4 receptor's function is essential for regulating neurotransmitter levels like dopamine and glutamate. Aiming targeting the M4 receptor offers a fresh treatment approach as it helps to significantly reduce cognitive problems.

Early Clinical Drug Development and Challenges

Early drug development targeting the M4 receptor primarily focused on acetylcholine receptor agonists, especially drugs targeting the M1 and M4 receptors. Xanomeline is one of the most representative drugs; it is a dual M1/M4 receptor agonist that has shown potential in improving cognitive function in clinical trials for Alzheimer's disease. However, Xanomeline also brought significant side effects, notably gastrointestinal discomfort due to its peripheral cholinergic action, which limits its clinical use.

Nevertheless, Xanomeline demonstrated unexpected effects in improving cognitive symptoms of schizophrenia. Subsequent clinical studies revealed that activating M1 and M4 receptors could effectively improve cognitive function and some positive symptoms in schizophrenia patients. These findings provide a theoretical basis for further developing drugs specifically targeting the M4 receptor.

Drug Development Targeting M4 Receptor: From Challenges to Opportunities

With a deeper understanding of mAChR's structure and function, researchers have gradually shifted their focus to the selective modulation of the M4 receptor. Because of their great structural conservation across mAChR subtypes, early drug development suffered from low selectivity. Consequently, creating medications that specifically target the M4 receptor has taken the front stage in research.

The development of highly selective M4 receptor agonists and allosteric modulators functioning on the M4 receptor dominates much of the current drug development aimed at the M4 receptor. Through attaching to their allosteric sites, allosteric modulators may control M4 receptor function, therefore preventing adverse effects from directly activating all receptor subtypes. Recent developments in these modulators provide treatment of schizophrenia fresh hope.

Future Outlook and Challenges

Many difficulties still exist even if preclinical and clinical phases of M4 receptor-targeted treatment show some favorable results. First of all, further research on possible side effects in targeted treatment is necessary regarding the complicated distribution and functional control of M4 receptors in the central nervous system. Second, further research is needed to maximize medication selectivity and effectiveness by employing interactions between M4 receptors and other cholinergic receptors.

Drugs targeting the M4 receptor are predicted to make significant breakthroughs in the treatment of neuropsychiatric diseases including schizophrenia in the future with developments in precision medicine and individualized therapy. More efficient and fewer side effects treatment strategies may be created by fully understanding the mechanics of the M4 receptor, therefore enhancing patients' cognitive capacities and quality of life.

References:

  1. Dean B. IUPHAR Review on muscarinic M1 and M4 receptors as drug treatment targets relevant to the molecular pathology of schizophrenia. Pharmacol Res. Published online November 19, 2024.
  2. Gibbons A, Dean B. The Cholinergic System: An Emerging Drug Target for Schizophrenia. Curr Pharm Des. 2016;22(14):2124-2133.
  3. Yohn SE, Harvey PD, et al. The potential of muscarinic M1 and M4 receptor activators for the treatment of cognitive impairment associated with schizophrenia. Front Psychiatry. 2024;15:1421554.
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