CHRM4, also known as cholinergic receptor muscarinic 4, is a G-protein-coupled receptor. It is involved in multiple biological processes. In the nervous system, it may play a role in cognitive processes as part of the cholinergic signaling pathway [4]. In hematopoiesis, it regulates the self-renewal of early erythroid progenitors like burst-forming unit erythroid (BFU-E) [5].

In prostate cancer, several studies have revealed its significance. After androgen-deprivation therapy (ADT), CHRM4 is highly expressed in prostate cancer cells. It can drive neuroendocrine differentiation of prostate cancer cells. Mechanistically, CHRM4-driven AKT/MYCN signaling upregulates interferon alpha 17 (IFNA17) in the tumor microenvironment (TME) after ADT, which in turn activates the CHRM4/AKT/MYCN-driven immune checkpoint pathway and promotes neuroendocrine differentiation [1]. Nerve growth factor (NGF) interacts with CHRM4 after ADT, regulating NEPC differentiation, and CHRM4 stimulation is associated with ADT resistance [2]. Also, the interaction of interleukin-1 receptor antagonist (IL1RN) with CHRM4 in prostate cancer after ADT activates the MAPK/AKT signaling pathway, leading to immunosuppression and neuroendocrine differentiation [3].

In conclusion, CHRM4 has diverse functions in different biological systems. In prostate cancer, its role in promoting neuroendocrine differentiation and immunosuppression through various signaling pathways is well-studied. Understanding CHRM4 may provide new therapeutic strategies for prostate cancer treatment. Genetic models such as gene knockout mouse models could potentially further elucidate its functions in different disease contexts as suggested by the research on its role in hematopoiesis and prostate cancer [1,2,3,5].

References:

1. Wen, Yu-Ching, Tram, Van Thi Ngoc, Chen, Wei-Hao, Chen, Wei-Yu, Liu, Yen-Nien. 2023. CHRM4/AKT/MYCN upregulates interferon alpha-17 in the tumor microenvironment to promote neuroendocrine differentiation of prostate cancer. In Cell death & disease, 14, 304. doi:10.1038/s41419-023-05836-7. https://pubmed.ncbi.nlm.nih.gov/37142586/

2. Chen, Wei-Yu, Wen, Yu-Ching, Lin, Shian-Ren, Huang, Jiaoti, Liu, Yen-Nien. 2021. Nerve growth factor interacts with CHRM4 and promotes neuroendocrine differentiation of prostate cancer and castration resistance. In Communications biology, 4, 22. doi:10.1038/s42003-020-01549-1. https://pubmed.ncbi.nlm.nih.gov/33398073/

3. Liu, Yen-Nien, Liu, Ming-Kun, Wen, Yu-Ching, Huang, Jiaoti, Chen, Wei-Yu. 2024. Binding of interleukin-1 receptor antagonist to cholinergic receptor muscarinic 4 promotes immunosuppression and neuroendocrine differentiation in prostate cancer. In Cancer letters, 598, 217090. doi:10.1016/j.canlet.2024.217090. https://pubmed.ncbi.nlm.nih.gov/38945201/

4. Reale, Marcella, Carrarini, Claudia, Russo, Mirella, Onofrj, Marco, Bonanni, Laura. . Muscarinic Receptors Expression in the Peripheral Blood Cells Differentiate Dementia with Lewy Bodies from Alzheimer's Disease. In Journal of Alzheimer's disease : JAD, 85, 323-330. doi:10.3233/JAD-215285. https://pubmed.ncbi.nlm.nih.gov/34806612/

5. Trivedi, Gaurang, Inoue, Daichi, Chen, Cynthia, Abdel-Wahab, Omar, Zhang, Lingbo. . Muscarinic acetylcholine receptor regulates self-renewal of early erythroid progenitors. In Science translational medicine, 11, . doi:10.1126/scitranslmed.aaw3781. https://pubmed.ncbi.nlm.nih.gov/31554738/