{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMelanin‐concentrating hormone receptor 1 (MCHR1) is a G protein‐coupled receptor that plays a central role in controlling energy homeostasis, feeding behavior, and emotional processing. Studies in HEK293 cells have demonstrated that MCHR1 couples to both Gᵢ and G_q proteins, leading to inhibition of adenylate cyclase activity and modulation of ERK signaling. Detailed ligand studies have defined a minimal “active core” of MCH that is sufficient to engage and activate MCHR1 and have further enabled the development of selective agonists that preferentially target the receptor."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nProper receptor folding and cell surface trafficking are critical for its function. A point mutation (T255A) impairs MCHR1 membrane expression due to misfolding and aberrant glycosylation, although pharmacological chaperones can restore its activity with preserved G_q coupling. In parallel, naturally occurring missense variants and common single‐nucleotide polymorphisms located in MCHR1 have been investigated for their association with obesity and psychiatric disorders. While some mutations (e.g., R248Q) and SNP haplotypes co‐segregate with severe early‐onset obesity and possibly influence downstream signaling, other genetic studies report inconsistent metabolic effects and significant associations with susceptibility to schizophrenia or bipolar disorder."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its central actions, MCHR1 is expressed in several peripheral tissues. In immune cells, its activation stimulates cAMP production and calcium mobilization, leading to immunomodulatory effects such as reduced T-cell proliferation. In human skin, expression of MCHR1 in melanocytes modulates melanogenesis by antagonizing the α-MSH–induced cAMP increase, while distinct receptor binding sites have been identified in keratinocyte-derived cells. Moreover, in dermal fibroblasts, PDGF-BB upregulates MCHR1, thereby contributing to profibrotic responses through enhanced production of TGF-β₁ and CTGF, suggesting a role in systemic sclerosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, MCHR1 function is modulated through interactions with intracellular proteins. The receptor directly binds periplakin, an interaction that influences its ability to couple to G proteins and initiate downstream signaling, while association with MIZIP links MCHR1 to tubulin, potentially affecting cytoskeletal dynamics. In addition, naturally occurring loss-of-function mutations (such as R210H and P377S) further underscore the importance of correct receptor structure for signal initiation, and regulatory proteins like RGS2 and RGS8 fine-tune the strength and duration of G_q-mediated calcium responses. Localization of MCHR1 to lipid rafts and its interaction with caveolin-1 emphasize the significance of membrane microdomains in orchestrating its signal transduction."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nImmunologically, several studies have identified autoantibodies against defined MCHR1 epitopes in patients with vitiligo, highlighting a potential role for the receptor in autoimmune pathology. Although investigations into other pathologies, such as nonsyndromic hearing loss, did not reveal a contributory role for MCHR1, and while research into neuronal mRNA cap methylation defines distinct regulatory pathways, the diverse findings across experimental systems reinforce the multifaceted influence of MCHR1 on cellular signaling, metabolism, and disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Pavlos Pissios, Daniel J Trombly, Iphigenia Tzameli, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Short segment of human melanin-concentrating hormone that is sufficient for full activation of human melanin-concentrating hormone receptors 1 and 2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi010867p"}], "href": "https://doi.org/10.1021/bi010867p"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11478907"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11478907"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Maria A Bednarek, Carina Tan, Donna L Hreniuk, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "The gene encoding the melanin-concentrating hormone receptor 1 is associated with schizophrenia in a Danish case-control sample."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Psychiatr Genet (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/YPG.0b013e32834dc424"}], "href": "https://doi.org/10.1097/YPG.0b013e32834dc424"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22081064"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22081064"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Myriam Verlaet, Antoine Adamantidis, Bernard Coumans, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human immune cells express ppMCH mRNA and functional MCHR1 receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0014-5793(02)03232-5"}], "href": "https://doi.org/10.1016/s0014-5793(02"}, {"type": "t", "text": "03232-5) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12220661"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12220661"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Martin J Hoogduijn, Janis Ancans, Itaru Suzuki, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "SVK14 cells express an MCH binding site different from the MCH1 or MCH2 receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0006-291x(02)00763-5"}], "href": "https://doi.org/10.1016/s0006-291x(02"}, {"type": "t", "text": "00763-5) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12127971"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12127971"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Hannah Murdoch, Gui-Jie Feng, Dietmar Bächner, et al. 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