CHRM4 Membrane Protein Introduction

Introduction of CHRM4

CHRM4, encoded by CHRM4 gene, is a member of G protein-coupled receptors family which has seven distinctive transmembrane domains. It is one of five subtypes of muscarinic receptors (CHRM1-5), selectively expressed in various human tissues. It has been found that muscarinic receptors are the potential therapeutic targets for a variety of pathological conditions, especially in neurodegenerative disorders.

Function of CHRM4 Membrane Protein

CHRM4, encoded by CHRM4 gene, belongs to a larger family of G protein-coupled receptors. It acts as an inhibitor of adenylyl cyclase which involves various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Moreover, muscarinic receptors affect many effects of acetylcholine in the central and peripheral nervous system. The study has shown that CHRM4 plays a key role in the progression of schizophrenia disease and the expression of CHRM4 is decreased in the hippocampus and caudate-putamen from patients with schizophrenia. Besides, CHRM4 is associated with the asthma occurrence and the expression of CHRM4 is significantly increased in asthmatic children. In addition, the CHRM4 acts as a drug target and prognostic marker for schizophrenia. Studies have implicated that M4 receptors can act as drug targets for neurodegenerative diseases and M4 receptors activators can be used as promising therapeutic drugs for central nervous system diseases.

Fig.1 Canonical signaling of muscarinic receptors. (Ockenga, 2013)

Application of CHRM4 Membrane Protein in Literature

1. Felder C C., et al. Current status of muscarinic M1 and M4 receptors as drug targets for neurodegenerative diseases. Neuropharmacology. 2018, 136(Pt C): 449-458. PubMed ID: 29374561
   
   

   The study reveals that M1 and M4 muscarinic acetylcholine receptors can act as promising drug targets for treating neurodegenerative and neuropsychiatric diseases. Compared to M1 muscarinic acetylcholine receptors, M4 muscarinic acetylcholine receptors are paid less attention. But M4 muscarinic acetylcholine receptors agonists are being explored.

2. Takai K., et al. Discovery and development of muscarinic acetylcholine M4 activators as promising therapeutic agents for CNS diseases. Chemical & Pharmaceutical Bulletin. 2018, 66(1): 37-44. PubMed ID: 29311510
   
   

   Due to the high homology of the orthosteric binding site among all muscarinic receptors, the authors identify M4 mAChR activators, orthosteric agonists, and positive allosteric modulators based on M4 mAChR structural information and structure-activity relationship studies. It indicates that selective M4 mAChR activators are the potential drugs for treating several central nervous system conditions.

3. Joseph L., et al. Effects of muscarinic receptor antagonists on cocaine discrimination in wild-type mice and in muscarinic receptor M1, M2, and M4 receptor knockout mice. Behavioural Brain Research. 2017, 329: 75-83. PubMed ID: 28442355
   
   

   The article suggests that stimulation of M1 receptors and M4 receptors can each decrease the (discriminative stimulus) S^D effect of cocaine. Moreover, inhibition of M2 autoreceptors can also reduce S^D effect of cocaine.

4. Levran O., et al. African-specific variability in the acetylcholine muscarinic receptor M4: association with cocaine and heroin addiction. Pharmacogenomics. 2016, 17(9): 995-1003. PubMed ID: 27269905
   
   

   The author analyzes the correlation between African-specific 55 polymorphisms and cocaine and heroin addiction. Results show that variants in CHRM4 are significantly associated with drug dependence. And it is proposed that CHRM4 variants may act as potential pharmacogenetic markers.

5. Waqar M., et al. In silico analysis of binding interaction of mamba toxins with M4 and M2 muscarinic acetylcholine receptors for therapeutic use in Alzheimer's disease. CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets. 2015, 14(8): 1031-40. PubMed ID: 26295818
   
   

   The study focuses on the M4 and M2 muscarinic acetylcholine autoreceptors potential use as targets in treating cognitive symptoms associated with Alzheimer's disease. Experiment data shows that mamba toxins bind to active site residues of M4 and M2 muscarinic acetylcholine autoreceptors. Thus, the author proposes that M4 and M2 muscarinic acetylcholine autoreceptors may act as the potential targets for mamba toxins antagonists.

CHRM4 Preparation Options

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Reference

1. Ockenga W, et al. (2013). Non-neuronal functions of the m2 muscarinic acetylcholine receptor. Genes. 4(2): 171-197.

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