{"gene":"MCHR1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1999,"finding":"The orphan G-protein-coupled receptor SLC-1 (MCHR1) was identified as the cognate receptor for melanin-concentrating hormone (MCH): SLC-1 expressed in HEK293 cells binds MCH with sub-nanomolar affinity, and MCH stimulates intracellular Ca2+ mobilization and reduces forskolin-elevated cAMP levels via this receptor.","method":"Radioligand binding assay, Ca2+ mobilization assay, cAMP assay in HEK293 cells expressing SLC-1","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal functional assays (binding, Ca2+, cAMP) in transfected cells, independently replicated by at least three additional labs in the same year","pmids":["10421367"],"is_preprint":false},{"year":1999,"finding":"MCHR1 (SLC-1) couples to both Gi/Go (GIRK-mediated currents) and Gq (PLC-mediated Ca2+-dependent Cl- currents) signal transduction pathways when expressed in Xenopus oocytes, demonstrating dual G-protein coupling.","method":"Xenopus oocyte expression system with co-expressed GIRK channels; electrophysiological recording of GIRK-mediated and Ca2+-dependent Cl- currents after MCH stimulation; ligand isolation by cation exchange chromatography and HPLC with mass spectrometry","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted signaling in Xenopus oocyte system with two orthogonal current measurements; dual coupling corroborated by independent labs","pmids":["10471841"],"is_preprint":false},{"year":1999,"finding":"MCH was isolated and identified as the endogenous ligand of the SLC-1 receptor by purifying rat brain extracts and demonstrating dose-dependent inhibition of forskolin-stimulated cAMP accumulation in CHO cells expressing rat and human SLC-1, with EC50 of 0.2 nM for both species.","method":"HPLC purification of rat brain extract; cAMP inhibition assay in CHO cells stably expressing SLC-1","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — ligand isolation from native tissue combined with functional cAMP assay; replicated across multiple labs","pmids":["10441476"],"is_preprint":false},{"year":2001,"finding":"Structure-activity relationship studies on MCHR1 (SLC-1) identified the minimal MCH sequence required for full agonism as MCH-(6-17) (the ring structure), with residues Met8, Arg11, and Tyr13 being essential for full potency in both cAMP inhibition and [35S]-GTPγS binding assays. Disruption of the disulfide bridge by Asp/Lys substitution eliminated agonist activity and produced weak micromolar antagonists.","method":"cAMP inhibition assay and [35S]-GTPγS binding on HEK293 cells stably expressing human MCHR1; alanine scanning and deletion mutagenesis of MCH peptide analogues","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — two orthogonal binding/functional assays with systematic mutagenesis of 57 analogues; single lab but rigorous SAR","pmids":["11278733"],"is_preprint":false},{"year":2001,"finding":"Agonist potencies of MCH analogues at the rat recombinant SLC-1 receptor (cAMP inhibition and radioligand binding) strongly correlated with in vivo feeding effects in rats upon intracerebroventricular injection, establishing SLC-1 as the mediator of MCH orexigenic actions.","method":"cAMP inhibition assay and [125I]S36057 binding on rat recombinant SLC-1; intracerebroventricular injection of MCH analogues with food intake measurement","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro receptor pharmacology correlated with in vivo feeding assay using matched analogue panel; single lab with two orthogonal approaches","pmids":["11561073"],"is_preprint":false},{"year":2001,"finding":"In SK-MEL-37 melanoma cells expressing endogenous SLC-1 (MCHR1), MCH inhibited cAMP and induced p42/p44 MAPK activation in a pertussis toxin-sensitive manner, but did not increase intracellular Ca2+, indicating selective coupling to Gαi/Gαo (not Gαq) in this cellular context. Overexpression studies in CHO and HEK293 cells confirmed SLC-1 can couple to both Gαi/Gαo and Gαq.","method":"cAMP inhibition assay, MAPK activation assay, Ca2+ mobilization assay, pertussis toxin treatment, cDNA transfection in CHO and 293 cells","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal signaling assays with pertussis toxin mechanistic probe; cell-context-dependent coupling demonstrated","pmids":["11708774"],"is_preprint":false},{"year":2002,"finding":"MCHR1 expressed in human peripheral blood mononuclear cells (PBMCs) couples to cAMP synthesis and calcium mobilization upon MCH stimulation, and MCH treatment decreases CD3-stimulated PBMC proliferation in vitro, indicating an immunomodulatory function of MCHR1.","method":"FACS, cAMP assay, Ca2+ mobilization assay, RT-PCR, in vitro PBMC proliferation assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple assays (cAMP, Ca2+, proliferation) in primary human immune cells; single lab","pmids":["12220661"],"is_preprint":false},{"year":2002,"finding":"Rhesus monkey MCH-R1 binds MCH with Kd of 6.5 nM and couples through both Gi/Go and Gq-type G proteins, mirroring human MCH-R1 signaling properties.","method":"Radioligand binding assay, intracellular signaling assays in cells expressing cloned rhesus MCH-R1","journal":"Peptides","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding and functional signaling assays; single lab, recapitulates human receptor data","pmids":["12182940"],"is_preprint":false},{"year":2004,"finding":"MCHR1-deficient mice develop osteoporosis characterized by reduced cortical bone mass and increased bone resorption (elevated serum c-telopeptide), indicating that MCHR1 signaling tonically stimulates cortical bone mass.","method":"Genetic knockout (MCHR1-/- mice), bone mass measurement, serum c-telopeptide assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined phenotypic readout (cortical bone loss, bone resorption marker); single lab","pmids":["15147966"],"is_preprint":false},{"year":2005,"finding":"Mch1r-deficient mice show enhanced voluntary wheel running activity, and Pmch-deficient mice also exhibit increased running activity, establishing that endogenous MCH acting through MCH1R inhibits locomotor activity. Naloxone suppressed wheel running in both genotypes, suggesting opioid regulation; wheel running increased dynorphin mRNA in Mch1r-/- brain.","method":"Voluntary wheel running assay in Mch1r-/- and Pmch-/- knockout mice; naloxone injection; dynorphin mRNA measurement","journal":"Regulatory peptides","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent genetic knockout lines with behavioral readout; single lab","pmids":["15544841"],"is_preprint":false},{"year":2006,"finding":"MCHR1 knockout mice display anxiolytic-like behavior across multiple paradigms (open field, elevated plus maze, social interaction, stress-induced hyperthermia), and show lower basal serotonin efflux in the prefrontal cortex and absent stress-induced 5-HT release compared to wild-types, linking MCHR1 signaling to serotonergic modulation of anxiety.","method":"MCHR1 knockout genetics, behavioral testing (open field, elevated plus maze, social interaction, stress-induced hyperthermia), in vivo microdialysis of 5-HT in prefrontal cortex","journal":"Neuropsychopharmacology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal behavioral paradigms plus in vivo neurochemistry in KO vs WT; single lab but comprehensive and internally consistent","pmids":["15988472"],"is_preprint":false},{"year":2006,"finding":"In a neuronal-derived cell line (I3.4.2) expressing MCHR1, MCH-stimulated Ca2+ mobilization was insensitive to pertussis toxin, indicating signaling via Gαq rather than Gαi/o; cAMP assays confirmed absence of Gαi/o coupling in this neural context, suggesting the coupling profile of MCHR1 is cell-type dependent.","method":"Ca2+ mobilization assay, cAMP assay, pertussis toxin treatment, [125I]MCH saturation binding in neural-derived I3.4.2 cell line","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling assays with pertussis toxin mechanistic probe in neural cell line; single lab","pmids":["16524757"],"is_preprint":false},{"year":2020,"finding":"MCHR1 protein is abundantly localized to the primary cilium of neurons throughout the CNS (olfactory bulb, cortex, striatum, hippocampus, amygdala, thalamus, hypothalamus, midbrain, spinal cord), as demonstrated by immunohistochemistry with a validated antibody, and ciliary MCHR1 is co-expressed with diverse neurochemical markers including tyrosine hydroxylase, calretinin, kisspeptin, estrogen receptor, oxytocin, vasopressin, and CRF.","method":"Immunohistochemistry with antibody validation; co-labeling with multiple neurochemical markers in rat and mouse brain","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with validated antibody and multiple neurochemical co-labels; single lab","pmids":["32530066"],"is_preprint":false},{"year":2021,"finding":"The ciliary transition zone protein AHI1 is required for trafficking of MCHR1 into neuronal primary cilia: Ahi1-/- neurons show significantly reduced ciliary MCHR1 without change in total or surface expression. Neurons lacking ciliary MCHR1 have significantly reduced MCH-stimulated cAMP and ERK signaling, establishing that ciliary localization of MCHR1 is necessary for its downstream signaling.","method":"Neuronal cultures from Ahi1+/+ and Ahi1-/- embryonic mice; immunofluorescence for ciliary vs total/surface MCHR1; cAMP assay; ERK activation assay after MCH stimulation","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function (Ahi1-/-) with quantitative localization data and two orthogonal downstream signaling readouts (cAMP and ERK); single lab but multiple orthogonal methods","pmids":["33741721"],"is_preprint":false},{"year":2021,"finding":"PDGF-BB binds directly to MCHR1 in membrane fractions of normal human dermal fibroblasts (confirmed by surface plasmon resonance), and MCHR1 mediates PDGF-BB-induced upregulation of TGFβ1 and CTGF (profibrotic factors) and modulation of intracellular cAMP; MCHR1 silencing reduced PDGF-BB signaling, identifying MCHR1 as a mediator of PDGF-BB-driven fibrotic responses.","method":"MCHR1 silencing (siRNA) in primary human dermal fibroblasts; mRNA/protein expression; surface plasmon resonance for PDGF-BB/MCHR1 binding; cAMP assay","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by SPR plus functional KD with cAMP and profibrotic gene readouts; single lab with multiple methods","pmids":["34912333"],"is_preprint":false},{"year":2022,"finding":"MRAP2 physically interacts with MCHR1 (demonstrated by co-immunoprecipitation and bimolecular fluorescence complementation) and inhibits MCHR1 signaling in vitro. The C-terminal domain of MRAP2 is required for pharmacological modulation of intracellular Ca2+ cascades and membrane transport of MCHR1.","method":"Co-immunoprecipitation, bimolecular fluorescence complementation assay, functional truncation analysis of MRAP2 C-terminus, intracellular Ca2+ assay","journal":"Frontiers in endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction confirmed by two orthogonal methods (Co-IP and BiFC) plus functional truncation mapping; single lab","pmids":["35311242"],"is_preprint":false},{"year":2012,"finding":"Disruption of MCH1R in mice leads to hypothyroidism: MCH1R-KO mice have reduced circulating iodothyronines (T4, free T4, T3, rT3) with elevated TRH and TSH, and their thyroid follicles sequester more hormone and secrete less T4 upon TSH challenge or 125I loading, indicating that MCHR1 signaling regulates thyroid hormone secretion.","method":"MCH1R knockout mice, serum hormone measurements, thyroid follicle size analysis, T4/T3 content in thyroid glands, TSH challenge and 125I secretion assay","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple endocrine readouts in KO mice with functional secretion challenge; single lab","pmids":["23024261"],"is_preprint":false}],"current_model":"MCHR1 (SLC-1/GPR24/MCH1R) is a G protein-coupled receptor that serves as the primary receptor for the neuropeptide MCH, binding it with sub-nanomolar affinity and coupling to both Gαi/o (inhibiting adenylyl cyclase, activating GIRK channels) and Gαq (mobilizing intracellular Ca2+ via PLC) in a cell-type-dependent manner; it is prominently localized to neuronal primary cilia via AHI1-dependent trafficking, where ciliary localization is required for MCH-stimulated cAMP and ERK signaling; MRAP2 interacts with MCHR1 through its C-terminus and inhibits its signaling; MCHR1 also acts as a binding partner and signaling mediator for PDGF-BB in dermal fibroblasts; and in vivo, MCHR1 signaling tonically regulates energy homeostasis, locomotor activity, anxiety/stress responses (via serotonergic modulation in prefrontal cortex), cortical bone mass, and thyroid hormone secretion."},"narrative":{"mechanistic_narrative":"MCHR1 (SLC-1/GPR24) is the cognate G protein-coupled receptor for the neuropeptide melanin-concentrating hormone (MCH), which it binds with sub-nanomolar affinity to control energy homeostasis and a range of CNS and endocrine functions [PMID:10421367, PMID:10441476]. Ligand engagement requires the MCH ring structure (residues spanning MCH-6-17, with Met8, Arg11, and Tyr13 critical for full agonism), and disruption of the peptide disulfide bridge abolishes agonism [PMID:11278733]. The receptor displays cell-type-dependent G-protein coupling: it engages both Gαi/o (inhibiting adenylyl cyclase and activating GIRK currents) and Gαq (mobilizing intracellular Ca2+ through PLC), with some contexts showing selective Gαi/o coupling (melanoma cells) and others selective Gαq coupling (neuronal lines) [PMID:10471841, PMID:11708774, PMID:16524757]. In CNS neurons, MCHR1 is concentrated in the primary cilium, where AHI1-dependent trafficking into the cilium is required for MCH-stimulated cAMP and ERK signaling [PMID:32530066, PMID:33741721]. Receptor activity is restrained by MRAP2, which physically interacts via its C-terminus to inhibit MCHR1 signaling and modulate its membrane transport [PMID:35311242]. Beyond MCH, MCHR1 binds PDGF-BB directly in dermal fibroblasts and mediates PDGF-BB-driven profibrotic responses [PMID:34912333]. In vivo, MCHR1 signaling tonically regulates locomotor activity, anxiety via serotonergic modulation in prefrontal cortex, cortical bone mass, and thyroid hormone secretion [PMID:15544841, PMID:15988472, PMID:15147966, PMID:23024261].","teleology":[{"year":1999,"claim":"Deorphanized the receptor SLC-1 by establishing MCH as its cognate ligand, defining the molecular entry point for MCH signaling.","evidence":"Radioligand binding, Ca2+ and cAMP assays in HEK293/CHO cells expressing SLC-1; ligand purification from rat brain extract","pmids":["10421367","10441476"],"confidence":"High","gaps":["Did not resolve the structural basis of MCH binding","Endogenous tissue distribution of the receptor not mapped"]},{"year":1999,"claim":"Demonstrated that MCHR1 couples to two distinct G-protein pathways, establishing dual signaling capacity.","evidence":"Xenopus oocyte expression with GIRK channels; electrophysiology of GIRK-mediated and Ca2+-dependent Cl- currents","pmids":["10471841"],"confidence":"High","gaps":["Did not establish which coupling dominates in native cells","Determinants of pathway selection unknown"]},{"year":2001,"claim":"Mapped the minimal agonist determinants of MCH and correlated receptor pharmacology with in vivo feeding, linking MCHR1 to orexigenic action.","evidence":"cAMP inhibition and [35S]-GTPγS/radioligand assays with MCH analogue mutagenesis; ICV injection with food intake measurement","pmids":["11278733","11561073"],"confidence":"High","gaps":["Receptor residues contacting the key MCH residues not defined","Did not identify the neural circuit mediating feeding"]},{"year":2002,"claim":"Showed that MCHR1 coupling profile is cell-context dependent and operates outside the CNS, including immune cells.","evidence":"cAMP, MAPK, Ca2+ assays with pertussis toxin in melanoma cells; cAMP/Ca2+/proliferation assays in human PBMCs","pmids":["11708774","12220661"],"confidence":"Medium","gaps":["Mechanism dictating Gαi/o vs Gαq selection unresolved","Physiological relevance of immune signaling not tested in vivo"]},{"year":2012,"claim":"Defined physiological outputs of MCHR1 signaling through knockout phenotyping across bone, locomotion, anxiety, and thyroid axes.","evidence":"MCHR1/Pmch knockout mice with bone mass, wheel running, behavioral paradigms, microdialysis, and thyroid hormone secretion assays","pmids":["15147966","15544841","15988472","23024261"],"confidence":"Medium","gaps":["Did not pinpoint the cell types mediating each phenotype","Downstream signaling linking receptor to each output not traced"]},{"year":2021,"claim":"Established ciliary localization as a requirement for MCHR1 signaling and identified AHI1 as the trafficking factor.","evidence":"Immunohistochemistry of ciliary MCHR1 across brain regions; Ahi1-/- neurons with ciliary localization, cAMP, and ERK readouts","pmids":["32530066","33741721"],"confidence":"High","gaps":["Molecular mechanism of AHI1-mediated ciliary entry not resolved","Whether ciliary requirement applies to all physiological outputs untested"]},{"year":2022,"claim":"Identified regulatory and non-canonical partners of MCHR1: the accessory protein MRAP2 as a signaling inhibitor and PDGF-BB as a direct binding ligand in fibroblasts.","evidence":"Co-IP, BiFC and C-terminal truncation for MRAP2; SPR binding and siRNA knockdown with profibrotic gene/cAMP readouts for PDGF-BB","pmids":["35311242","34912333"],"confidence":"Medium","gaps":["Structural basis of MRAP2 and PDGF-BB interactions undefined","In vivo relevance of PDGF-BB/MCHR1 axis not established"]},{"year":null,"claim":"How MCHR1 selects between Gαi/o and Gαq in different cell types, and how ciliary localization and accessory proteins integrate to determine its physiological outputs, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of agonist-bound MCHR1","Mechanism of cell-type-specific G-protein selection unknown","Link between ciliary signaling and specific in vivo phenotypes uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[12,13]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,14]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,5]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[10,12,13]}],"complexes":[],"partners":["MCH","AHI1","MRAP2","PDGFB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99705","full_name":"Melanin-concentrating hormone receptor 1","aliases":["G-protein coupled receptor 24","MCH-1R","MCH1R","MCHR","SLC-1","Somatostatin receptor-like protein"],"length_aa":353,"mass_kda":38.9,"function":"Receptor for melanin-concentrating hormone, coupled to both G proteins that inhibit adenylyl cyclase and G proteins that activate phosphoinositide hydrolysis","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q99705/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MCHR1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MCHR1","total_profiled":1310},"omim":[{"mim_id":"611424","title":"ZINC FINGER MYND DOMAIN-CONTAINING PROTEIN 19; ZMYND19","url":"https://www.omim.org/entry/611424"},{"mim_id":"606151","title":"BBS2 GENE; BBS2","url":"https://www.omim.org/entry/606151"},{"mim_id":"606111","title":"MELANIN-CONCENTRATING HORMONE RECEPTOR 2; MCHR2","url":"https://www.omim.org/entry/606111"},{"mim_id":"601751","title":"MELANIN-CONCENTRATING HORMONE RECEPTOR 1; MCHR1","url":"https://www.omim.org/entry/601751"},{"mim_id":"600374","title":"BBS4 GENE; BBS4","url":"https://www.omim.org/entry/600374"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":9.3},{"tissue":"endometrium 1","ntpm":5.5},{"tissue":"ovary","ntpm":9.9}],"url":"https://www.proteinatlas.org/search/MCHR1"},"hgnc":{"alias_symbol":["SLC1","MCH1R"],"prev_symbol":["GPR24"]},"alphafold":{"accession":"Q99705","domains":[{"cath_id":"1.20.1070.10","chopping":"103-392","consensus_level":"high","plddt":91.272,"start":103,"end":392}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99705","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99705-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99705-F1-predicted_aligned_error_v6.png","plddt_mean":84.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MCHR1","jax_strain_url":"https://www.jax.org/strain/search?query=MCHR1"},"sequence":{"accession":"Q99705","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99705.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99705/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99705"}},"corpus_meta":[{"pmid":"10421367","id":"PMC_10421367","title":"Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1.","date":"1999","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/10421367","citation_count":419,"is_preprint":false},{"pmid":"10762350","id":"PMC_10762350","title":"The distribution of the mRNA and protein products of the melanin-concentrating hormone (MCH) receptor gene, slc-1, in the central nervous system of the rat.","date":"2000","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/10762350","citation_count":240,"is_preprint":false},{"pmid":"10471841","id":"PMC_10471841","title":"Identification of melanin concentrating hormone (MCH) as the natural ligand for the orphan somatostatin-like receptor 1 (SLC-1).","date":"1999","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/10471841","citation_count":163,"is_preprint":false},{"pmid":"10441476","id":"PMC_10441476","title":"Isolation and identification of melanin-concentrating hormone as the endogenous ligand of the SLC-1 receptor.","date":"1999","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10441476","citation_count":145,"is_preprint":false},{"pmid":"17675291","id":"PMC_17675291","title":"SLC1 and SLC4 encode partially redundant acyl-coenzyme A 1-acylglycerol-3-phosphate O-acyltransferases of budding yeast.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17675291","citation_count":102,"is_preprint":false},{"pmid":"17237257","id":"PMC_17237257","title":"Efficacy of the MCHR1 antagonist N-[3-(1-{[4-(3,4-difluorophenoxy)phenyl]methyl}(4-piperidyl))-4-methylphenyl]-2-methylpropanamide (SNAP 94847) in mouse models of anxiety and depression following acute and chronic administration is independent of hippocampal neurogenesis.","date":"2007","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/17237257","citation_count":100,"is_preprint":false},{"pmid":"24240778","id":"PMC_24240778","title":"SLC1 glutamate transporters.","date":"2013","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/24240778","citation_count":86,"is_preprint":false},{"pmid":"24586162","id":"PMC_24586162","title":"The Chlamydia trachomatis type III secretion chaperone Slc1 engages multiple early effectors, including TepP, a tyrosine-phosphorylated protein required for the recruitment of CrkI-II to nascent inclusions and innate immune signaling.","date":"2014","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/24586162","citation_count":84,"is_preprint":false},{"pmid":"15988472","id":"PMC_15988472","title":"Genetic inactivation of melanin-concentrating hormone receptor subtype 1 (MCHR1) in mice exerts anxiolytic-like behavioral effects.","date":"2006","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/15988472","citation_count":82,"is_preprint":false},{"pmid":"17655875","id":"PMC_17655875","title":"Anti-obesity effects of small molecule melanin-concentrating hormone receptor 1 (MCHR1) antagonists.","date":"2007","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/17655875","citation_count":62,"is_preprint":false},{"pmid":"9531978","id":"PMC_9531978","title":"Cloning of the rat brain cDNA encoding for the SLC-1 G protein-coupled receptor reveals the presence of an intron in the gene.","date":"1998","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/9531978","citation_count":61,"is_preprint":false},{"pmid":"16934771","id":"PMC_16934771","title":"A study of the involvement of melanin-concentrating hormone receptor 1 (MCHR1) in murine models of depression.","date":"2006","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/16934771","citation_count":60,"is_preprint":false},{"pmid":"15544841","id":"PMC_15544841","title":"Enhanced running wheel activity of both Mch1r- and Pmch-deficient mice.","date":"2005","source":"Regulatory peptides","url":"https://pubmed.ncbi.nlm.nih.gov/15544841","citation_count":58,"is_preprint":false},{"pmid":"20582487","id":"PMC_20582487","title":"Recent updates on the melanin-concentrating hormone (MCH) and its receptor system: lessons from MCH1R antagonists.","date":"2010","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/20582487","citation_count":55,"is_preprint":false},{"pmid":"11278733","id":"PMC_11278733","title":"Structure-activity relationship studies of melanin-concentrating hormone (MCH)-related peptide ligands at SLC-1, the human MCH receptor.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11278733","citation_count":54,"is_preprint":false},{"pmid":"20628734","id":"PMC_20628734","title":"Suppression of alcohol self-administration and reinstatement of alcohol seeking by melanin-concentrating hormone receptor 1 (MCH1-R) antagonism in Wistar rats.","date":"2010","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20628734","citation_count":50,"is_preprint":false},{"pmid":"20429920","id":"PMC_20429920","title":"Phylogenetic analysis of the vertebrate excitatory/neutral amino acid transporter (SLC1/EAAT) family reveals lineage specific subfamilies.","date":"2010","source":"BMC evolutionary biology","url":"https://pubmed.ncbi.nlm.nih.gov/20429920","citation_count":49,"is_preprint":false},{"pmid":"26741166","id":"PMC_26741166","title":"Discovery of (3-(4-(2-Oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone (AZD1979), a Melanin Concentrating Hormone Receptor 1 (MCHr1) Antagonist with Favorable Physicochemical Properties.","date":"2016","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26741166","citation_count":45,"is_preprint":false},{"pmid":"21849510","id":"PMC_21849510","title":"Topology of 1-acyl-sn-glycerol-3-phosphate acyltransferases SLC1 and ALE1 and related membrane-bound O-acyltransferases (MBOATs) of Saccharomyces cerevisiae.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21849510","citation_count":42,"is_preprint":false},{"pmid":"12220661","id":"PMC_12220661","title":"Human immune cells express ppMCH mRNA and functional MCHR1 receptor.","date":"2002","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/12220661","citation_count":41,"is_preprint":false},{"pmid":"11561073","id":"PMC_11561073","title":"SLC-1 receptor mediates effect of melanin-concentrating hormone on feeding behavior in rat: a structure-activity study.","date":"2001","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/11561073","citation_count":40,"is_preprint":false},{"pmid":"21637341","id":"PMC_21637341","title":"Allele-specific, age-dependent and BMI-associated DNA methylation of human MCHR1.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21637341","citation_count":36,"is_preprint":false},{"pmid":"28419191","id":"PMC_28419191","title":"PPARδ promotes tumor progression via activation of Glut1 and SLC1-A5 transcription.","date":"2017","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/28419191","citation_count":36,"is_preprint":false},{"pmid":"15341943","id":"PMC_15341943","title":"Synthesis and evaluation of 2-amino-8-alkoxy quinolines as MCHr1 antagonists. Part 2.","date":"2004","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/15341943","citation_count":36,"is_preprint":false},{"pmid":"11708774","id":"PMC_11708774","title":"Endogenous melanin-concentrating hormone receptor SLC-1 in human melanoma SK-MEL-37 cells.","date":"2001","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11708774","citation_count":33,"is_preprint":false},{"pmid":"21883523","id":"PMC_21883523","title":"Chlamydia trachomatis Slc1 is a type III secretion chaperone that enhances the translocation of its invasion effector substrate TARP.","date":"2011","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/21883523","citation_count":31,"is_preprint":false},{"pmid":"8628245","id":"PMC_8628245","title":"Molecular and genetic characterization of SLC1, a putative Saccharomyces cerevisiae homolog of the metazoan cytoplasmic dynein light chain 1.","date":"1996","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/8628245","citation_count":30,"is_preprint":false},{"pmid":"22705492","id":"PMC_22705492","title":"Melanin-concentrating hormone receptor 1 (MCH1-R) antagonism: reduced appetite for calories and suppression of addictive-like behaviors.","date":"2012","source":"Pharmacology, biochemistry, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/22705492","citation_count":30,"is_preprint":false},{"pmid":"18767801","id":"PMC_18767801","title":"Enantioselective synthesis of SNAP-7941: chiral dihydropyrimidone inhibitor of MCH1-R.","date":"2008","source":"The Journal of organic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18767801","citation_count":30,"is_preprint":false},{"pmid":"22954736","id":"PMC_22954736","title":"Melanin concentrating hormone receptor 1 (MCHR1) antagonists-Still a viable approach for obesity treatment?","date":"2012","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/22954736","citation_count":27,"is_preprint":false},{"pmid":"15341942","id":"PMC_15341942","title":"Synthesis and evaluation of 2-amino-8-alkoxy quinolines as MCHr1 antagonists. Part 1.","date":"2004","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/15341942","citation_count":25,"is_preprint":false},{"pmid":"32530066","id":"PMC_32530066","title":"Ciliary melanin-concentrating hormone receptor 1 (MCHR1) is widely distributed in the murine CNS in a sex-independent manner.","date":"2020","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/32530066","citation_count":24,"is_preprint":false},{"pmid":"15147966","id":"PMC_15147966","title":"Osteoporosis in MCHR1-deficient mice.","date":"2004","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15147966","citation_count":23,"is_preprint":false},{"pmid":"15941924","id":"PMC_15941924","title":"Mutation analysis of the MCHR1 gene in human obesity.","date":"2005","source":"European journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/15941924","citation_count":22,"is_preprint":false},{"pmid":"19768478","id":"PMC_19768478","title":"Changes in oil content of transgenic soybeans expressing the yeast SLC1 gene.","date":"2009","source":"Lipids","url":"https://pubmed.ncbi.nlm.nih.gov/19768478","citation_count":22,"is_preprint":false},{"pmid":"30335150","id":"PMC_30335150","title":"Melanin-Concentrating Hormone (MCH) and MCH-R1 in the Locus Coeruleus May Be Involved in the Regulation of Depressive-Like Behavior.","date":"2018","source":"The international journal of neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30335150","citation_count":22,"is_preprint":false},{"pmid":"34912333","id":"PMC_34912333","title":"PDGF Promotes Dermal Fibroblast Activation via a Novel Mechanism Mediated by Signaling Through MCHR1.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34912333","citation_count":21,"is_preprint":false},{"pmid":"12182940","id":"PMC_12182940","title":"Cloning and characterization of rhesus monkey MCH-R1 and MCH-R2.","date":"2002","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/12182940","citation_count":21,"is_preprint":false},{"pmid":"22487182","id":"PMC_22487182","title":"Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists.","date":"2012","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/22487182","citation_count":21,"is_preprint":false},{"pmid":"17270288","id":"PMC_17270288","title":"Exploratory activity, motor coordination, and spatial learning in Mchr1 knockout mice.","date":"2007","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/17270288","citation_count":20,"is_preprint":false},{"pmid":"16741940","id":"PMC_16741940","title":"Association analyses suggest GPR24 as a shared susceptibility gene for bipolar affective disorder and schizophrenia.","date":"2006","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16741940","citation_count":19,"is_preprint":false},{"pmid":"22921745","id":"PMC_22921745","title":"[¹⁸F]FE@SNAP-A new PET tracer for the melanin concentrating hormone receptor 1 (MCHR1): microfluidic and vessel-based approaches.","date":"2012","source":"Bioorganic & medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22921745","citation_count":19,"is_preprint":false},{"pmid":"22542010","id":"PMC_22542010","title":"Discovery of a novel melanin concentrating hormone receptor 1 (MCHR1) antagonist with reduced hERG inhibition.","date":"2012","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/22542010","citation_count":15,"is_preprint":false},{"pmid":"23590178","id":"PMC_23590178","title":"Fighting obesity with a sugar-based library: discovery of novel MCH-1R antagonists by a new computational-VAST approach for exploration of GPCR binding sites.","date":"2013","source":"Journal of chemical information and modeling","url":"https://pubmed.ncbi.nlm.nih.gov/23590178","citation_count":15,"is_preprint":false},{"pmid":"22249825","id":"PMC_22249825","title":"Antiobesity effects of melanin-concentrating hormone receptor 1 (MCH-R1) antagonists.","date":"2012","source":"Handbook of experimental pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/22249825","citation_count":14,"is_preprint":false},{"pmid":"22497763","id":"PMC_22497763","title":"Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists: part 2.","date":"2012","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/22497763","citation_count":13,"is_preprint":false},{"pmid":"17329101","id":"PMC_17329101","title":"Thienopyrimidinone bis-aminopyrrolidine ureas as potent melanin-concentrating hormone receptor-1 (MCH-R1) antagonists.","date":"2007","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/17329101","citation_count":13,"is_preprint":false},{"pmid":"33741721","id":"PMC_33741721","title":"The Transition Zone Protein AHI1 Regulates Neuronal Ciliary Trafficking of MCHR1 and Its Downstream Signaling Pathway.","date":"2021","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/33741721","citation_count":12,"is_preprint":false},{"pmid":"24106662","id":"PMC_24106662","title":"Preparation and First Preclinical Evaluation of [(18)F]FE@SNAP: A Potential PET Tracer for the Melanin-Concentrating Hormone Receptor-1 (MCHR1).","date":"2013","source":"Scientia pharmaceutica","url":"https://pubmed.ncbi.nlm.nih.gov/24106662","citation_count":12,"is_preprint":false},{"pmid":"27564419","id":"PMC_27564419","title":"Synthesis and Antiobesity Properties of 6-(4-Chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (BMS-814580): A Highly Efficacious Melanin Concentrating Hormone Receptor 1 (MCHR1) Inhibitor.","date":"2016","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27564419","citation_count":12,"is_preprint":false},{"pmid":"17234405","id":"PMC_17234405","title":"An evaluation of 3,4-methylenedioxy phenyl replacements in the aminopiperidine chromone class of MCHr1 antagonists.","date":"2006","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/17234405","citation_count":12,"is_preprint":false},{"pmid":"22858577","id":"PMC_22858577","title":"Radiosynthesis of [11C]SNAP-7941--the first PET-tracer for the melanin concentrating hormone receptor 1 (MCHR1).","date":"2012","source":"Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22858577","citation_count":12,"is_preprint":false},{"pmid":"15950467","id":"PMC_15950467","title":"Synthesis and structure-activity relationships of biarylcarboxamide bis-aminopyrrolidine urea derived small-molecule antagonists of the melanin-concentrating hormone receptor-1 (MCH-R1).","date":"2005","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/15950467","citation_count":12,"is_preprint":false},{"pmid":"16919453","id":"PMC_16919453","title":"4-Aminoquinoline melanin-concentrating hormone 1-receptor (MCH1R) antagonists.","date":"2006","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/16919453","citation_count":11,"is_preprint":false},{"pmid":"21802292","id":"PMC_21802292","title":"Strategies to lower the Pgp efflux liability in a series of potent indole azetidine MCHR1 antagonists.","date":"2011","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/21802292","citation_count":11,"is_preprint":false},{"pmid":"17350253","id":"PMC_17350253","title":"Identification of diamino chromone-2-carboxamides as MCHr1 antagonists with minimal hERG channel activity.","date":"2006","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/17350253","citation_count":11,"is_preprint":false},{"pmid":"17407817","id":"PMC_17407817","title":"Novel series of substituted biphenylmethyl urea derivatives as MCH-R1 antagonists for the treatment of obesity.","date":"2007","source":"Bioorganic & medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17407817","citation_count":11,"is_preprint":false},{"pmid":"20635163","id":"PMC_20635163","title":"Anxiolytic effects of the MCH1R antagonist TPI 1361-17.","date":"2010","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/20635163","citation_count":10,"is_preprint":false},{"pmid":"15340116","id":"PMC_15340116","title":"Identification and characterization of single-nucleotide polymorphisms in MCH-R1 and MCH-R2.","date":"2004","source":"Obesity research","url":"https://pubmed.ncbi.nlm.nih.gov/15340116","citation_count":10,"is_preprint":false},{"pmid":"22377519","id":"PMC_22377519","title":"An example of designed multiple ligands spanning protein classes: dual MCH-1R antagonists/DPPIV inhibitors.","date":"2012","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/22377519","citation_count":10,"is_preprint":false},{"pmid":"19500982","id":"PMC_19500982","title":"Optimization of piperidin-4-yl-urea-containing melanin-concentrating hormone receptor 1 (MCH-R1) antagonists: Reducing hERG-associated liabilities.","date":"2009","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/19500982","citation_count":10,"is_preprint":false},{"pmid":"35311242","id":"PMC_35311242","title":"Determination of the Interaction and Pharmacological Modulation of MCHR1 Signaling by the C-Terminus of MRAP2 Protein.","date":"2022","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/35311242","citation_count":9,"is_preprint":false},{"pmid":"16524757","id":"PMC_16524757","title":"Characterization of a neuronal cell line expressing native human melanin-concentrating hormone receptor 1 (MCHR1).","date":"2006","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16524757","citation_count":9,"is_preprint":false},{"pmid":"25505557","id":"PMC_25505557","title":"Evaluation of AMG 076, a potent and selective MCHR1 antagonist, in rodent and primate obesity models.","date":"2013","source":"Pharmacology research & perspectives","url":"https://pubmed.ncbi.nlm.nih.gov/25505557","citation_count":9,"is_preprint":false},{"pmid":"20724156","id":"PMC_20724156","title":"Discovery of novel, orally available benzimidazoles as melanin concentrating hormone receptor 1 (MCHR1) antagonists.","date":"2010","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/20724156","citation_count":9,"is_preprint":false},{"pmid":"16824755","id":"PMC_16824755","title":"Synthesis and structure-activity relationships of retro bis-aminopyrrolidine urea (rAPU) derived small-molecule antagonists of the melanin-concentrating hormone receptor-1 (MCH-R1). Part 2.","date":"2006","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/16824755","citation_count":9,"is_preprint":false},{"pmid":"18198296","id":"PMC_18198296","title":"Single nucleotide polymorphisms of the MCHR1 gene do not affect metabolism in humans.","date":"2007","source":"Obesity (Silver Spring, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/18198296","citation_count":8,"is_preprint":false},{"pmid":"20932767","id":"PMC_20932767","title":"Building a MCHR1 homology model provides insight into the receptor-antagonist contacts that are important for the development of new anti-obesity agents.","date":"2010","source":"Bioorganic & medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20932767","citation_count":8,"is_preprint":false},{"pmid":"17897030","id":"PMC_17897030","title":"Aminoquinoline melanin-concentrating hormone 1-receptor (MCH1-R) antagonists.","date":"2007","source":"Current topics in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17897030","citation_count":8,"is_preprint":false},{"pmid":"19500979","id":"PMC_19500979","title":"Optimization of 2-piperidin-4-yl-acetamides as melanin-concentrating hormone receptor 1 (MCH-R1) antagonists: Designing out hERG inhibition.","date":"2009","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/19500979","citation_count":8,"is_preprint":false},{"pmid":"21420863","id":"PMC_21420863","title":"Synthesis and SAR investigations of novel 2-arylbenzimidazole derivatives as melanin-concentrating hormone receptor 1 (MCH-R1) antagonists.","date":"2011","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/21420863","citation_count":8,"is_preprint":false},{"pmid":"16879961","id":"PMC_16879961","title":"Identification of substituted 4-aminopiperidines and 3-aminopyrrolidines as potent MCH-R1 antagonists for the treatment of obesity.","date":"2006","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/16879961","citation_count":8,"is_preprint":false},{"pmid":"21369690","id":"PMC_21369690","title":"Immunodetection of the MCHR1 antibody in vitiligo patient sera.","date":"2011","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21369690","citation_count":7,"is_preprint":false},{"pmid":"35409167","id":"PMC_35409167","title":"Identification and New Indication of Melanin-Concentrating Hormone Receptor 1 (MCHR1) Antagonist Derived from Machine Learning and Transcriptome-Based Drug Repositioning Approaches.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35409167","citation_count":7,"is_preprint":false},{"pmid":"19361985","id":"PMC_19361985","title":"Identification and characterization of a selective radioligand for melanin-concentrating hormone 1-receptor (MCH1R).","date":"2009","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/19361985","citation_count":7,"is_preprint":false},{"pmid":"20411353","id":"PMC_20411353","title":"Acute homeostatic responses to increased fat consumption in MCH1R knockout mice.","date":"2010","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/20411353","citation_count":7,"is_preprint":false},{"pmid":"19457661","id":"PMC_19457661","title":"Identification of 2-aminobenzimidazoles as potent melanin-concentrating hormone 1-receptor (MCH1R) antagonists.","date":"2009","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/19457661","citation_count":7,"is_preprint":false},{"pmid":"22137790","id":"PMC_22137790","title":"4-arylphthalazin-1(2H)-one derivatives as potent antagonists of the melanin concentrating hormone receptor 1 (MCH-R1).","date":"2011","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/22137790","citation_count":7,"is_preprint":false},{"pmid":"16814542","id":"PMC_16814542","title":"Synthesis and structure-activity relationships of retro bis-aminopyrrolidine urea (rAPU) derived small-molecule antagonists of the melanin-concentrating hormone receptor-1 (MCH-R1). Part 1.","date":"2006","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/16814542","citation_count":7,"is_preprint":false},{"pmid":"37269945","id":"PMC_37269945","title":"Saccharomyces cerevisiae Δ9-desaturase Ole1 forms a supercomplex with Slc1 and Dga1.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37269945","citation_count":6,"is_preprint":false},{"pmid":"28626527","id":"PMC_28626527","title":"Systematic Data Mining Reveals Synergistic H3R/MCHR1 Ligands.","date":"2017","source":"ACS medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/28626527","citation_count":6,"is_preprint":false},{"pmid":"33673598","id":"PMC_33673598","title":"MCH-R1 Antagonist GPS18169, a Pseudopeptide, Is a Peripheral Anti-Obesity Agent in Mice.","date":"2021","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/33673598","citation_count":6,"is_preprint":false},{"pmid":"25257526","id":"PMC_25257526","title":"Profiling the interaction mechanism of quinoline/quinazoline derivatives as MCHR1 antagonists: an in silico method.","date":"2014","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25257526","citation_count":6,"is_preprint":false},{"pmid":"24084017","id":"PMC_24084017","title":"Syntheses of precursors and reference compounds of the melanin-concentrating hormone receptor 1 (MCHR1) tracers [¹¹C]SNAP-7941 and [¹⁸F]FE@SNAP for positron emission tomography.","date":"2013","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/24084017","citation_count":6,"is_preprint":false},{"pmid":"17350839","id":"PMC_17350839","title":"Synthesis and structure-activity relationships of spirohydantoin-derived small-molecule antagonists of the melanin-concentrating hormone receptor-1 (MCH-R1).","date":"2007","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/17350839","citation_count":6,"is_preprint":false},{"pmid":"18682323","id":"PMC_18682323","title":"Discovery of 1,3-disubstituted-1H-pyrrole derivatives as potent melanin-concentrating hormone receptor 1 (MCH-R1) antagonists.","date":"2008","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/18682323","citation_count":6,"is_preprint":false},{"pmid":"31244769","id":"PMC_31244769","title":"In vitro Radiopharmaceutical Evidence for MCHR1 Binding Sites in Murine Brown Adipocytes.","date":"2019","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/31244769","citation_count":5,"is_preprint":false},{"pmid":"27595423","id":"PMC_27595423","title":"Evolution of physicochemical properties of melanin concentrating hormone receptor 1 (MCHr1) antagonists.","date":"2016","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/27595423","citation_count":5,"is_preprint":false},{"pmid":"35041296","id":"PMC_35041296","title":"hERG Optimization of Benzofuro-Pyridine and Pyrazino-Indole Derivatives as MCHR1 Antagonists.","date":"2022","source":"ChemMedChem","url":"https://pubmed.ncbi.nlm.nih.gov/35041296","citation_count":5,"is_preprint":false},{"pmid":"32329245","id":"PMC_32329245","title":"PyRod Enables Rational Homology Model-based Virtual Screening Against MCHR1.","date":"2020","source":"Molecular informatics","url":"https://pubmed.ncbi.nlm.nih.gov/32329245","citation_count":5,"is_preprint":false},{"pmid":"12680590","id":"PMC_12680590","title":"Different structural requirements for melanin-concentrating hormone (MCH) interacting with rat MCH-R1 (SLC-1) and mouse B16 cell MCH-R.","date":"2003","source":"Journal of receptor and signal transduction research","url":"https://pubmed.ncbi.nlm.nih.gov/12680590","citation_count":5,"is_preprint":false},{"pmid":"17897031","id":"PMC_17897031","title":"Melanin concentrating hormone receptor antagonists as antiobesity agents: from M2 to MCHR-1.","date":"2007","source":"Current topics in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17897031","citation_count":5,"is_preprint":false},{"pmid":"23411080","id":"PMC_23411080","title":"Synthesis and SAR study of pyrrolo[3,4-b]pyridin-7(6H)-one derivatives as melanin concentrating hormone receptor 1 (MCH-R1) antagonists.","date":"2013","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/23411080","citation_count":5,"is_preprint":false},{"pmid":"23024261","id":"PMC_23024261","title":"Disruption of the melanin-concentrating hormone receptor 1 (MCH1R) affects thyroid function.","date":"2012","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/23024261","citation_count":4,"is_preprint":false},{"pmid":"36565982","id":"PMC_36565982","title":"Acute intrahippocampal administration of melanin-concentrating hormone impairs memory consolidation and decreases the expression of MCHR-1 and TrkB receptors.","date":"2022","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/36565982","citation_count":4,"is_preprint":false},{"pmid":"28025230","id":"PMC_28025230","title":"Mechanisms for Hepatobiliary Toxicity in Rats Treated with an Antagonist of Melanin Concentrating Hormone Receptor 1 (MCHR1).","date":"2016","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/28025230","citation_count":4,"is_preprint":false},{"pmid":"26022839","id":"PMC_26022839","title":"Dihydropyrrolopyrazol-6-one MCHR1 antagonists for the treatment of obesity: Insights on in vivo efficacy from a novel FLIPR assay setup.","date":"2015","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/26022839","citation_count":4,"is_preprint":false},{"pmid":"29948643","id":"PMC_29948643","title":"SNAPshots of the MCHR1: a Comparison Between the PET-Tracers [18F]FE@SNAP and [11C]SNAP-7941.","date":"2019","source":"Molecular imaging and biology","url":"https://pubmed.ncbi.nlm.nih.gov/29948643","citation_count":3,"is_preprint":false},{"pmid":"39892319","id":"PMC_39892319","title":"The 1-acylglycerol-3-phosphate acyltransferase Slc1 is required to regulate mitochondria and lipid droplets.","date":"2025","source":"Microbiological research","url":"https://pubmed.ncbi.nlm.nih.gov/39892319","citation_count":3,"is_preprint":false},{"pmid":"8701613","id":"PMC_8701613","title":"Physical mapping of a centromere-proximal region of chromosome IV-L defines the placement of genes USO1, MBP1, PSA1 and SLC1.","date":"1996","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/8701613","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":41416,"output_tokens":4499,"usd":0.095866,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12564,"output_tokens":2705,"usd":0.065223,"stage2_stop_reason":"end_turn"},"total_usd":0.161089,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"The orphan G-protein-coupled receptor SLC-1 (MCHR1) was identified as the cognate receptor for melanin-concentrating hormone (MCH): SLC-1 expressed in HEK293 cells binds MCH with sub-nanomolar affinity, and MCH stimulates intracellular Ca2+ mobilization and reduces forskolin-elevated cAMP levels via this receptor.\",\n      \"method\": \"Radioligand binding assay, Ca2+ mobilization assay, cAMP assay in HEK293 cells expressing SLC-1\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal functional assays (binding, Ca2+, cAMP) in transfected cells, independently replicated by at least three additional labs in the same year\",\n      \"pmids\": [\"10421367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MCHR1 (SLC-1) couples to both Gi/Go (GIRK-mediated currents) and Gq (PLC-mediated Ca2+-dependent Cl- currents) signal transduction pathways when expressed in Xenopus oocytes, demonstrating dual G-protein coupling.\",\n      \"method\": \"Xenopus oocyte expression system with co-expressed GIRK channels; electrophysiological recording of GIRK-mediated and Ca2+-dependent Cl- currents after MCH stimulation; ligand isolation by cation exchange chromatography and HPLC with mass spectrometry\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted signaling in Xenopus oocyte system with two orthogonal current measurements; dual coupling corroborated by independent labs\",\n      \"pmids\": [\"10471841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MCH was isolated and identified as the endogenous ligand of the SLC-1 receptor by purifying rat brain extracts and demonstrating dose-dependent inhibition of forskolin-stimulated cAMP accumulation in CHO cells expressing rat and human SLC-1, with EC50 of 0.2 nM for both species.\",\n      \"method\": \"HPLC purification of rat brain extract; cAMP inhibition assay in CHO cells stably expressing SLC-1\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ligand isolation from native tissue combined with functional cAMP assay; replicated across multiple labs\",\n      \"pmids\": [\"10441476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Structure-activity relationship studies on MCHR1 (SLC-1) identified the minimal MCH sequence required for full agonism as MCH-(6-17) (the ring structure), with residues Met8, Arg11, and Tyr13 being essential for full potency in both cAMP inhibition and [35S]-GTPγS binding assays. Disruption of the disulfide bridge by Asp/Lys substitution eliminated agonist activity and produced weak micromolar antagonists.\",\n      \"method\": \"cAMP inhibition assay and [35S]-GTPγS binding on HEK293 cells stably expressing human MCHR1; alanine scanning and deletion mutagenesis of MCH peptide analogues\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — two orthogonal binding/functional assays with systematic mutagenesis of 57 analogues; single lab but rigorous SAR\",\n      \"pmids\": [\"11278733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Agonist potencies of MCH analogues at the rat recombinant SLC-1 receptor (cAMP inhibition and radioligand binding) strongly correlated with in vivo feeding effects in rats upon intracerebroventricular injection, establishing SLC-1 as the mediator of MCH orexigenic actions.\",\n      \"method\": \"cAMP inhibition assay and [125I]S36057 binding on rat recombinant SLC-1; intracerebroventricular injection of MCH analogues with food intake measurement\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro receptor pharmacology correlated with in vivo feeding assay using matched analogue panel; single lab with two orthogonal approaches\",\n      \"pmids\": [\"11561073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In SK-MEL-37 melanoma cells expressing endogenous SLC-1 (MCHR1), MCH inhibited cAMP and induced p42/p44 MAPK activation in a pertussis toxin-sensitive manner, but did not increase intracellular Ca2+, indicating selective coupling to Gαi/Gαo (not Gαq) in this cellular context. Overexpression studies in CHO and HEK293 cells confirmed SLC-1 can couple to both Gαi/Gαo and Gαq.\",\n      \"method\": \"cAMP inhibition assay, MAPK activation assay, Ca2+ mobilization assay, pertussis toxin treatment, cDNA transfection in CHO and 293 cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal signaling assays with pertussis toxin mechanistic probe; cell-context-dependent coupling demonstrated\",\n      \"pmids\": [\"11708774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MCHR1 expressed in human peripheral blood mononuclear cells (PBMCs) couples to cAMP synthesis and calcium mobilization upon MCH stimulation, and MCH treatment decreases CD3-stimulated PBMC proliferation in vitro, indicating an immunomodulatory function of MCHR1.\",\n      \"method\": \"FACS, cAMP assay, Ca2+ mobilization assay, RT-PCR, in vitro PBMC proliferation assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple assays (cAMP, Ca2+, proliferation) in primary human immune cells; single lab\",\n      \"pmids\": [\"12220661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Rhesus monkey MCH-R1 binds MCH with Kd of 6.5 nM and couples through both Gi/Go and Gq-type G proteins, mirroring human MCH-R1 signaling properties.\",\n      \"method\": \"Radioligand binding assay, intracellular signaling assays in cells expressing cloned rhesus MCH-R1\",\n      \"journal\": \"Peptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding and functional signaling assays; single lab, recapitulates human receptor data\",\n      \"pmids\": [\"12182940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MCHR1-deficient mice develop osteoporosis characterized by reduced cortical bone mass and increased bone resorption (elevated serum c-telopeptide), indicating that MCHR1 signaling tonically stimulates cortical bone mass.\",\n      \"method\": \"Genetic knockout (MCHR1-/- mice), bone mass measurement, serum c-telopeptide assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined phenotypic readout (cortical bone loss, bone resorption marker); single lab\",\n      \"pmids\": [\"15147966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mch1r-deficient mice show enhanced voluntary wheel running activity, and Pmch-deficient mice also exhibit increased running activity, establishing that endogenous MCH acting through MCH1R inhibits locomotor activity. Naloxone suppressed wheel running in both genotypes, suggesting opioid regulation; wheel running increased dynorphin mRNA in Mch1r-/- brain.\",\n      \"method\": \"Voluntary wheel running assay in Mch1r-/- and Pmch-/- knockout mice; naloxone injection; dynorphin mRNA measurement\",\n      \"journal\": \"Regulatory peptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent genetic knockout lines with behavioral readout; single lab\",\n      \"pmids\": [\"15544841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MCHR1 knockout mice display anxiolytic-like behavior across multiple paradigms (open field, elevated plus maze, social interaction, stress-induced hyperthermia), and show lower basal serotonin efflux in the prefrontal cortex and absent stress-induced 5-HT release compared to wild-types, linking MCHR1 signaling to serotonergic modulation of anxiety.\",\n      \"method\": \"MCHR1 knockout genetics, behavioral testing (open field, elevated plus maze, social interaction, stress-induced hyperthermia), in vivo microdialysis of 5-HT in prefrontal cortex\",\n      \"journal\": \"Neuropsychopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal behavioral paradigms plus in vivo neurochemistry in KO vs WT; single lab but comprehensive and internally consistent\",\n      \"pmids\": [\"15988472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In a neuronal-derived cell line (I3.4.2) expressing MCHR1, MCH-stimulated Ca2+ mobilization was insensitive to pertussis toxin, indicating signaling via Gαq rather than Gαi/o; cAMP assays confirmed absence of Gαi/o coupling in this neural context, suggesting the coupling profile of MCHR1 is cell-type dependent.\",\n      \"method\": \"Ca2+ mobilization assay, cAMP assay, pertussis toxin treatment, [125I]MCH saturation binding in neural-derived I3.4.2 cell line\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling assays with pertussis toxin mechanistic probe in neural cell line; single lab\",\n      \"pmids\": [\"16524757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MCHR1 protein is abundantly localized to the primary cilium of neurons throughout the CNS (olfactory bulb, cortex, striatum, hippocampus, amygdala, thalamus, hypothalamus, midbrain, spinal cord), as demonstrated by immunohistochemistry with a validated antibody, and ciliary MCHR1 is co-expressed with diverse neurochemical markers including tyrosine hydroxylase, calretinin, kisspeptin, estrogen receptor, oxytocin, vasopressin, and CRF.\",\n      \"method\": \"Immunohistochemistry with antibody validation; co-labeling with multiple neurochemical markers in rat and mouse brain\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with validated antibody and multiple neurochemical co-labels; single lab\",\n      \"pmids\": [\"32530066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The ciliary transition zone protein AHI1 is required for trafficking of MCHR1 into neuronal primary cilia: Ahi1-/- neurons show significantly reduced ciliary MCHR1 without change in total or surface expression. Neurons lacking ciliary MCHR1 have significantly reduced MCH-stimulated cAMP and ERK signaling, establishing that ciliary localization of MCHR1 is necessary for its downstream signaling.\",\n      \"method\": \"Neuronal cultures from Ahi1+/+ and Ahi1-/- embryonic mice; immunofluorescence for ciliary vs total/surface MCHR1; cAMP assay; ERK activation assay after MCH stimulation\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function (Ahi1-/-) with quantitative localization data and two orthogonal downstream signaling readouts (cAMP and ERK); single lab but multiple orthogonal methods\",\n      \"pmids\": [\"33741721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PDGF-BB binds directly to MCHR1 in membrane fractions of normal human dermal fibroblasts (confirmed by surface plasmon resonance), and MCHR1 mediates PDGF-BB-induced upregulation of TGFβ1 and CTGF (profibrotic factors) and modulation of intracellular cAMP; MCHR1 silencing reduced PDGF-BB signaling, identifying MCHR1 as a mediator of PDGF-BB-driven fibrotic responses.\",\n      \"method\": \"MCHR1 silencing (siRNA) in primary human dermal fibroblasts; mRNA/protein expression; surface plasmon resonance for PDGF-BB/MCHR1 binding; cAMP assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by SPR plus functional KD with cAMP and profibrotic gene readouts; single lab with multiple methods\",\n      \"pmids\": [\"34912333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MRAP2 physically interacts with MCHR1 (demonstrated by co-immunoprecipitation and bimolecular fluorescence complementation) and inhibits MCHR1 signaling in vitro. The C-terminal domain of MRAP2 is required for pharmacological modulation of intracellular Ca2+ cascades and membrane transport of MCHR1.\",\n      \"method\": \"Co-immunoprecipitation, bimolecular fluorescence complementation assay, functional truncation analysis of MRAP2 C-terminus, intracellular Ca2+ assay\",\n      \"journal\": \"Frontiers in endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction confirmed by two orthogonal methods (Co-IP and BiFC) plus functional truncation mapping; single lab\",\n      \"pmids\": [\"35311242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Disruption of MCH1R in mice leads to hypothyroidism: MCH1R-KO mice have reduced circulating iodothyronines (T4, free T4, T3, rT3) with elevated TRH and TSH, and their thyroid follicles sequester more hormone and secrete less T4 upon TSH challenge or 125I loading, indicating that MCHR1 signaling regulates thyroid hormone secretion.\",\n      \"method\": \"MCH1R knockout mice, serum hormone measurements, thyroid follicle size analysis, T4/T3 content in thyroid glands, TSH challenge and 125I secretion assay\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple endocrine readouts in KO mice with functional secretion challenge; single lab\",\n      \"pmids\": [\"23024261\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MCHR1 (SLC-1/GPR24/MCH1R) is a G protein-coupled receptor that serves as the primary receptor for the neuropeptide MCH, binding it with sub-nanomolar affinity and coupling to both Gαi/o (inhibiting adenylyl cyclase, activating GIRK channels) and Gαq (mobilizing intracellular Ca2+ via PLC) in a cell-type-dependent manner; it is prominently localized to neuronal primary cilia via AHI1-dependent trafficking, where ciliary localization is required for MCH-stimulated cAMP and ERK signaling; MRAP2 interacts with MCHR1 through its C-terminus and inhibits its signaling; MCHR1 also acts as a binding partner and signaling mediator for PDGF-BB in dermal fibroblasts; and in vivo, MCHR1 signaling tonically regulates energy homeostasis, locomotor activity, anxiety/stress responses (via serotonergic modulation in prefrontal cortex), cortical bone mass, and thyroid hormone secretion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MCHR1 (SLC-1/GPR24) is the cognate G protein-coupled receptor for the neuropeptide melanin-concentrating hormone (MCH), which it binds with sub-nanomolar affinity to control energy homeostasis and a range of CNS and endocrine functions [#0, #2]. Ligand engagement requires the MCH ring structure (residues spanning MCH-6-17, with Met8, Arg11, and Tyr13 critical for full agonism), and disruption of the peptide disulfide bridge abolishes agonism [#3]. The receptor displays cell-type-dependent G-protein coupling: it engages both Gαi/o (inhibiting adenylyl cyclase and activating GIRK currents) and Gαq (mobilizing intracellular Ca2+ through PLC), with some contexts showing selective Gαi/o coupling (melanoma cells) and others selective Gαq coupling (neuronal lines) [#1, #5, #11]. In CNS neurons, MCHR1 is concentrated in the primary cilium, where AHI1-dependent trafficking into the cilium is required for MCH-stimulated cAMP and ERK signaling [#12, #13]. Receptor activity is restrained by MRAP2, which physically interacts via its C-terminus to inhibit MCHR1 signaling and modulate its membrane transport [#15]. Beyond MCH, MCHR1 binds PDGF-BB directly in dermal fibroblasts and mediates PDGF-BB-driven profibrotic responses [#14]. In vivo, MCHR1 signaling tonically regulates locomotor activity, anxiety via serotonergic modulation in prefrontal cortex, cortical bone mass, and thyroid hormone secretion [#9, #10, #8, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Deorphanized the receptor SLC-1 by establishing MCH as its cognate ligand, defining the molecular entry point for MCH signaling.\",\n      \"evidence\": \"Radioligand binding, Ca2+ and cAMP assays in HEK293/CHO cells expressing SLC-1; ligand purification from rat brain extract\",\n      \"pmids\": [\"10421367\", \"10441476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of MCH binding\", \"Endogenous tissue distribution of the receptor not mapped\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrated that MCHR1 couples to two distinct G-protein pathways, establishing dual signaling capacity.\",\n      \"evidence\": \"Xenopus oocyte expression with GIRK channels; electrophysiology of GIRK-mediated and Ca2+-dependent Cl- currents\",\n      \"pmids\": [\"10471841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish which coupling dominates in native cells\", \"Determinants of pathway selection unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Mapped the minimal agonist determinants of MCH and correlated receptor pharmacology with in vivo feeding, linking MCHR1 to orexigenic action.\",\n      \"evidence\": \"cAMP inhibition and [35S]-GTPγS/radioligand assays with MCH analogue mutagenesis; ICV injection with food intake measurement\",\n      \"pmids\": [\"11278733\", \"11561073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor residues contacting the key MCH residues not defined\", \"Did not identify the neural circuit mediating feeding\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed that MCHR1 coupling profile is cell-context dependent and operates outside the CNS, including immune cells.\",\n      \"evidence\": \"cAMP, MAPK, Ca2+ assays with pertussis toxin in melanoma cells; cAMP/Ca2+/proliferation assays in human PBMCs\",\n      \"pmids\": [\"11708774\", \"12220661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism dictating Gαi/o vs Gαq selection unresolved\", \"Physiological relevance of immune signaling not tested in vivo\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined physiological outputs of MCHR1 signaling through knockout phenotyping across bone, locomotion, anxiety, and thyroid axes.\",\n      \"evidence\": \"MCHR1/Pmch knockout mice with bone mass, wheel running, behavioral paradigms, microdialysis, and thyroid hormone secretion assays\",\n      \"pmids\": [\"15147966\", \"15544841\", \"15988472\", \"23024261\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not pinpoint the cell types mediating each phenotype\", \"Downstream signaling linking receptor to each output not traced\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established ciliary localization as a requirement for MCHR1 signaling and identified AHI1 as the trafficking factor.\",\n      \"evidence\": \"Immunohistochemistry of ciliary MCHR1 across brain regions; Ahi1-/- neurons with ciliary localization, cAMP, and ERK readouts\",\n      \"pmids\": [\"32530066\", \"33741721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of AHI1-mediated ciliary entry not resolved\", \"Whether ciliary requirement applies to all physiological outputs untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified regulatory and non-canonical partners of MCHR1: the accessory protein MRAP2 as a signaling inhibitor and PDGF-BB as a direct binding ligand in fibroblasts.\",\n      \"evidence\": \"Co-IP, BiFC and C-terminal truncation for MRAP2; SPR binding and siRNA knockdown with profibrotic gene/cAMP readouts for PDGF-BB\",\n      \"pmids\": [\"35311242\", \"34912333\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of MRAP2 and PDGF-BB interactions undefined\", \"In vivo relevance of PDGF-BB/MCHR1 axis not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MCHR1 selects between Gαi/o and Gαq in different cell types, and how ciliary localization and accessory proteins integrate to determine its physiological outputs, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of agonist-bound MCHR1\", \"Mechanism of cell-type-specific G-protein selection unknown\", \"Link between ciliary signaling and specific in vivo phenotypes uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [12, 13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [10, 12, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MCH\", \"AHI1\", \"MRAP2\", \"PDGFB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}