{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CHRM4, the muscarinic acetylcholine receptor M4, plays diverse roles in both neuronal and non‐neuronal systems. In the central nervous system, CHRM4 is expressed by striatal medium spiny neurons and contributes to their proper differentiation and organization, as its reduced expression parallels impaired neuronal maturation and disrupted striatal architecture."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Moreover, CHRM4 critically regulates dopaminergic signaling in striatal regions; in the nucleus accumbens CHRM4, along with other muscarinic subtypes, modulates the probability of dopamine release in response to cholinergic input."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Animal studies further demonstrate that loss of CHRM4 function results in behavioral alterations—including enhanced locomotor activity, deficits in sensorimotor gating, and abnormal social interactions—that implicate CHRM4 in the neural circuits underlying psychiatric conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n At the molecular level, specific sequences within the third intracellular loop of CHRM4 govern its internalization and recycling dynamics, which are essential for maintaining its signaling competence."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In non‐neuronal contexts, CHRM4 activity appears to negatively regulate early progenitor self‐renewal: inhibition of CHRM4 promotes self‐renewal of burst-forming unit–erythroid cells and corrects anemia associated with conditions such as myelodysplastic syndrome and aging."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Additionally, CHRM4 is highly enriched in gastric somatostatin-producing D-cells, suggesting a role in modulating hormone secretion in the gastrointestinal tract."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of neuropsychiatric disorders, particular CHRM4 gene polymorphisms have been associated with an increased risk of schizophrenia and with higher lifetime exposure to antipsychotic drugs, indicating that genetic variation in CHRM4 may contribute to disease susceptibility and treatment response."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Furthermore, in prostate cancer the nerve growth factor (NGF)–CHRM4 axis has been shown to promote neuroendocrine differentiation and activate oncogenic signaling pathways, suggesting that CHRM4 is a potential therapeutic target in neuroendocrine prostate cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, in skin biology, CHRM4 signaling facilitates keratinocyte migration and wound reepithelialization by modulating the expression of “migratory” integrins, further underscoring the receptor’s broad functional repertoire."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Paola Arlotta, Bradley J Molyneaux, Denis Jabaudon, et al. 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