{"gene":"MCHR2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2001,"finding":"MCHR2 (MCH-2R) binds MCH with high affinity and signals exclusively through Gαq coupling, as demonstrated by inositol phosphate turnover and intracellular calcium release in mammalian cells. Unlike MCH-1R, MCHR2 signaling is insensitive to pertussis toxin and does not reduce forskolin-stimulated cAMP production, indicating no Gi/Go coupling.","method":"Radioligand binding, inositol phosphate turnover assay, intracellular calcium assay, pertussis toxin treatment, cAMP assay in mammalian cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal functional assays (calcium, IP turnover, cAMP, pertussis toxin) replicated across two independent labs (PMIDs 11404457 and 11459838)","pmids":["11404457","11459838"],"is_preprint":false},{"year":2001,"finding":"MCH-R2 binds 125I-MCH specifically in CHO cells stably expressing the receptor and stimulates dose-dependent increases in intracellular Ca2+ and inositol phosphate but does not affect cAMP production. The pharmacological profile for salmon MCH at MCH-R2 differs from MCH-R1: salmon MCH EC50/IC50 is ~10-fold higher than mammalian MCH at MCH-R2, whereas these values are relatively similar at MCH-R1.","method":"Radioligand binding assay, intracellular calcium assay, inositol phosphate assay, cAMP assay in stable CHO cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal signaling assays with ligand selectivity profiling, independent replication of core findings","pmids":["11459838"],"is_preprint":false},{"year":2002,"finding":"Rhesus monkey MCH-R2 (98% homologous to human MCH-R2) binds MCH with a Kd of 2.2 nM and signals exclusively through the Gq pathway, consistent with human MCH-R2 and distinct from MCH-R1 which couples through both Gi/Go and Gq.","method":"Radioligand binding assay, intracellular signaling assays in cells expressing cloned receptors","journal":"Peptides","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding and functional signaling assays in a single lab, consistent with findings in human receptor studies","pmids":["12182940"],"is_preprint":false},{"year":2004,"finding":"Two MCHR2 coding SNPs (R63K in African-Americans; R152Q in whites) produce no detectable changes in receptor binding or functional signaling (cAMP, Ca2+) when expressed in CHO cells, indicating these variants do not alter receptor pharmacology.","method":"Site-directed mutagenesis of SNP variants, radioligand binding assay, cAMP assay, Ca2+ assay in CHO cells","journal":"Obesity research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional characterization of natural variants with multiple assays in a single lab; negative result is itself mechanistically informative","pmids":["15340116"],"is_preprint":false},{"year":2009,"finding":"Human MCHR2 expressed in CHO cells binds MCH with a Kd of 0.170 nM and a Bmax of ~310 fM/mg protein, and MCH stimulates intracellular Ca2+ release with an EC50 of 2.32 nM, confirming functional ligand-receptor coupling.","method":"Radioligand binding assay, intracellular Ca2+ assay in stable CHO cells expressing human MCHR2","journal":"Indian journal of experimental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — binding and calcium signaling assays in a single lab, single study, but consistent with earlier independent work","pmids":["20099459"],"is_preprint":false},{"year":2010,"finding":"shRNA-mediated knockdown of MCHR2 in CHO cells stably expressing human MCHR2 reduced receptor mRNA and protein by 45–66%, decreased MCH binding by 39–79%, reduced receptor–ligand affinity by 41–82%, and attenuated MCH-stimulated intracellular Ca2+ release, confirming that MCHR2 protein level directly controls downstream Gαq-mediated Ca2+ signaling.","method":"shRNA knockdown, radioligand binding assay, intracellular Ca2+ assay, RT-PCR, western blot","journal":"Cellular and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple orthogonal readouts (binding, affinity, Ca2+ signaling) in a single lab","pmids":["20937223"],"is_preprint":false}],"current_model":"MCHR2 is a human Gαq-coupled GPCR that binds melanin-concentrating hormone (MCH) with high affinity (Kd ~0.17–2.2 nM), activates phospholipase C to produce inositol phosphates and intracellular Ca2+ release, does not inhibit cAMP production, and is insensitive to pertussis toxin, distinguishing it mechanistically from the Gi/Go-coupled MCHR1; receptor expression level directly governs the magnitude of MCH-stimulated Ca2+ signaling."},"narrative":{"mechanistic_narrative":"MCHR2 is a G protein-coupled receptor for melanin-concentrating hormone (MCH) that transduces ligand binding into Gαq-mediated intracellular signaling [PMID:11404457, PMID:11459838]. It binds MCH with high affinity (Kd ~0.17–2.2 nM) and, upon activation, drives inositol phosphate turnover and intracellular Ca2+ release while leaving forskolin-stimulated cAMP production unaffected; its signaling is insensitive to pertussis toxin, establishing exclusive Gq coupling and distinguishing it mechanistically from the Gi/Go- and Gq-coupled MCHR1 [PMID:11404457, PMID:11459838]. The receptor discriminates ligand orthologs, with salmon MCH showing ~10-fold weaker potency than mammalian MCH at MCHR2 [PMID:11459838], and this Gq-restricted profile is conserved in the rhesus ortholog [PMID:12182940]. Receptor abundance directly governs signaling output: shRNA knockdown of MCHR2 proportionally reduces MCH binding, ligand affinity, and MCH-stimulated Ca2+ release [PMID:20937223]. Two natural coding variants (R63K, R152Q) do not alter binding or signaling [PMID:15340116]. Beyond ligand binding and proximal Gq/PLC/Ca2+ coupling, the physiological and tissue-level roles of MCHR2 have not been characterized in the available corpus.","teleology":[{"year":2001,"claim":"Established that MCHR2 is a bona fide MCH receptor and defined its G protein coupling, resolving how it differs signally from the previously known MCHR1.","evidence":"Radioligand binding, inositol phosphate turnover, intracellular Ca2+ and cAMP assays with pertussis toxin treatment in mammalian and stable CHO cells, across two independent labs","pmids":["11404457","11459838"],"confidence":"High","gaps":["Does not define the structural basis of Gq selectivity","Endogenous tissue context and physiological output not addressed","Ligand ortholog selectivity at MCHR2 only partly mapped"]},{"year":2001,"claim":"Showed MCHR2 distinguishes MCH orthologs pharmacologically, revealing receptor-specific ligand recognition not seen at MCHR1.","evidence":"Radioligand binding, Ca2+, IP and cAMP assays comparing salmon versus mammalian MCH potency in stable CHO cells","pmids":["11459838"],"confidence":"High","gaps":["Residues governing ortholog discrimination not identified","No structural model of the ligand-binding pocket"]},{"year":2002,"claim":"Demonstrated that the Gq-exclusive signaling mode is conserved across primates, supporting it as an intrinsic receptor property rather than a cell-context artifact.","evidence":"Radioligand binding (Kd 2.2 nM) and signaling assays of cloned rhesus MCH-R2 in expressing cells","pmids":["12182940"],"confidence":"Medium","gaps":["Single-lab characterization","No comparison of downstream physiology between species"]},{"year":2004,"claim":"Tested whether common coding variants alter receptor function, addressing a candidate-gene link to phenotypic variation.","evidence":"Site-directed mutagenesis of R63K and R152Q variants with binding, cAMP and Ca2+ assays in CHO cells","pmids":["15340116"],"confidence":"Medium","gaps":["Variants tested only in a heterologous system","No in vivo or expression-level consequences assessed"]},{"year":2009,"claim":"Provided refined quantitative binding and signaling parameters for the human receptor, anchoring affinity and potency values.","evidence":"Radioligand binding (Kd 0.170 nM) and intracellular Ca2+ assay (EC50 2.32 nM) in stable CHO cells","pmids":["20099459"],"confidence":"Medium","gaps":["Single study, single lab","No endogenous-cell measurements"]},{"year":2010,"claim":"Established that receptor protein abundance is rate-limiting for downstream signaling, linking expression level directly to Gq/Ca2+ output magnitude.","evidence":"shRNA knockdown in CHO cells with RT-PCR, western blot, radioligand binding and Ca2+ assays","pmids":["20937223"],"confidence":"Medium","gaps":["Demonstrated only in an overexpression CHO system","Does not address regulation of MCHR2 expression in native tissues"]},{"year":null,"claim":"The physiological roles, native tissue signaling, regulatory inputs, and structural basis of ligand recognition for MCHR2 remain undefined in the available corpus.","evidence":"","pmids":[],"confidence":"Low","gaps":["No in vivo functional studies","No structural data on ligand binding or Gq engagement","Endogenous expression and downstream physiology 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]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q969V1","full_name":"Melanin-concentrating hormone receptor 2","aliases":["G-protein coupled receptor 145","GPRv17","MCH-2R","MCH2","MCH2R"],"length_aa":340,"mass_kda":38.8,"function":"Receptor for melanin-concentrating hormone, coupled to G proteins that activate phosphoinositide hydrolysis","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q969V1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MCHR2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MCHR2","total_profiled":1310},"omim":[{"mim_id":"618373","title":"CANCER, ALOPECIA, PIGMENT DYSCRASIA, ONYCHODYSTROPHY, AND KERATODERMA; CAPOK","url":"https://www.omim.org/entry/618373"},{"mim_id":"612883","title":"MENARCHE, AGE AT, QUANTITATIVE TRAIT LOCUS 3; MENAQ3","url":"https://www.omim.org/entry/612883"},{"mim_id":"612882","title":"MENARCHE, AGE AT, QUANTITATIVE TRAIT LOCUS 2; MENAQ2","url":"https://www.omim.org/entry/612882"},{"mim_id":"606111","title":"MELANIN-CONCENTRATING HORMONE RECEPTOR 2; MCHR2","url":"https://www.omim.org/entry/606111"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"},{"location":"Primary cilium tip","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":5.1},{"tissue":"testis","ntpm":1.4}],"url":"https://www.proteinatlas.org/search/MCHR2"},"hgnc":{"alias_symbol":["SLT","MCH2","MCH2R"],"prev_symbol":["GPR145"]},"alphafold":{"accession":"Q969V1","domains":[{"cath_id":"1.20.1070.10","chopping":"31-325","consensus_level":"high","plddt":91.4701,"start":31,"end":325}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969V1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q969V1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q969V1-F1-predicted_aligned_error_v6.png","plddt_mean":88.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MCHR2","jax_strain_url":"https://www.jax.org/strain/search?query=MCHR2"},"sequence":{"accession":"Q969V1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q969V1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q969V1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969V1"}},"corpus_meta":[{"pmid":"11404457","id":"PMC_11404457","title":"Identification and characterization of a second melanin-concentrating hormone receptor, MCH-2R.","date":"2001","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11404457","citation_count":204,"is_preprint":false},{"pmid":"11459838","id":"PMC_11459838","title":"Identification and pharmacological characterization of a novel human melanin-concentrating hormone receptor, mch-r2.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11459838","citation_count":84,"is_preprint":false},{"pmid":"15313548","id":"PMC_15313548","title":"Why mice have lost genes for COL21A1, STK17A, GPR145 and AHRI: evidence for gene deletion at evolutionary breakpoints in the rodent lineage.","date":"2004","source":"Trends in genetics : TIG","url":"https://pubmed.ncbi.nlm.nih.gov/15313548","citation_count":28,"is_preprint":false},{"pmid":"17324419","id":"PMC_17324419","title":"The melanin-concentrating hormone receptor 2 (MCH-R2) mediates the effect of MCH to control body color for background adaptation in the barfin flounder.","date":"2007","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/17324419","citation_count":28,"is_preprint":false},{"pmid":"27306922","id":"PMC_27306922","title":"Genomewide analysis of copy number variants in alopecia areata in a Central European cohort reveals association with MCHR2.","date":"2017","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/27306922","citation_count":26,"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":"26461262","id":"PMC_26461262","title":"Influence of MCHR2 and MCHR2-AS1 Genetic Polymorphisms on Body Mass Index in Psychiatric Patients and In Population-Based Subjects with Present or Past Atypical Depression.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26461262","citation_count":16,"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":"29066024","id":"PMC_29066024","title":"DNA sequencing and copy number variation analysis of MCHR2 in a cohort of Prader Willi like (PWL) patients.","date":"2017","source":"Obesity research & clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/29066024","citation_count":2,"is_preprint":false},{"pmid":"20099459","id":"PMC_20099459","title":"Establishment of CHO cell line expressing human MCHR2 gene and research of its molecular characteristics.","date":"2009","source":"Indian journal of experimental biology","url":"https://pubmed.ncbi.nlm.nih.gov/20099459","citation_count":1,"is_preprint":false},{"pmid":"20937223","id":"PMC_20937223","title":"Generation of mammalian cell lines with gene knock-down for human MCHR2.","date":"2010","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/20937223","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7644,"output_tokens":1589,"usd":0.023384,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8353,"output_tokens":2103,"usd":0.04717,"stage2_stop_reason":"end_turn"},"total_usd":0.070554,"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\": 2001,\n      \"finding\": \"MCHR2 (MCH-2R) binds MCH with high affinity and signals exclusively through Gαq coupling, as demonstrated by inositol phosphate turnover and intracellular calcium release in mammalian cells. Unlike MCH-1R, MCHR2 signaling is insensitive to pertussis toxin and does not reduce forskolin-stimulated cAMP production, indicating no Gi/Go coupling.\",\n      \"method\": \"Radioligand binding, inositol phosphate turnover assay, intracellular calcium assay, pertussis toxin treatment, cAMP assay in mammalian cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal functional assays (calcium, IP turnover, cAMP, pertussis toxin) replicated across two independent labs (PMIDs 11404457 and 11459838)\",\n      \"pmids\": [\"11404457\", \"11459838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"MCH-R2 binds 125I-MCH specifically in CHO cells stably expressing the receptor and stimulates dose-dependent increases in intracellular Ca2+ and inositol phosphate but does not affect cAMP production. The pharmacological profile for salmon MCH at MCH-R2 differs from MCH-R1: salmon MCH EC50/IC50 is ~10-fold higher than mammalian MCH at MCH-R2, whereas these values are relatively similar at MCH-R1.\",\n      \"method\": \"Radioligand binding assay, intracellular calcium assay, inositol phosphate assay, cAMP assay in stable CHO cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal signaling assays with ligand selectivity profiling, independent replication of core findings\",\n      \"pmids\": [\"11459838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Rhesus monkey MCH-R2 (98% homologous to human MCH-R2) binds MCH with a Kd of 2.2 nM and signals exclusively through the Gq pathway, consistent with human MCH-R2 and distinct from MCH-R1 which couples through both Gi/Go and Gq.\",\n      \"method\": \"Radioligand binding assay, intracellular signaling assays in cells expressing cloned receptors\",\n      \"journal\": \"Peptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding and functional signaling assays in a single lab, consistent with findings in human receptor studies\",\n      \"pmids\": [\"12182940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Two MCHR2 coding SNPs (R63K in African-Americans; R152Q in whites) produce no detectable changes in receptor binding or functional signaling (cAMP, Ca2+) when expressed in CHO cells, indicating these variants do not alter receptor pharmacology.\",\n      \"method\": \"Site-directed mutagenesis of SNP variants, radioligand binding assay, cAMP assay, Ca2+ assay in CHO cells\",\n      \"journal\": \"Obesity research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional characterization of natural variants with multiple assays in a single lab; negative result is itself mechanistically informative\",\n      \"pmids\": [\"15340116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Human MCHR2 expressed in CHO cells binds MCH with a Kd of 0.170 nM and a Bmax of ~310 fM/mg protein, and MCH stimulates intracellular Ca2+ release with an EC50 of 2.32 nM, confirming functional ligand-receptor coupling.\",\n      \"method\": \"Radioligand binding assay, intracellular Ca2+ assay in stable CHO cells expressing human MCHR2\",\n      \"journal\": \"Indian journal of experimental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — binding and calcium signaling assays in a single lab, single study, but consistent with earlier independent work\",\n      \"pmids\": [\"20099459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"shRNA-mediated knockdown of MCHR2 in CHO cells stably expressing human MCHR2 reduced receptor mRNA and protein by 45–66%, decreased MCH binding by 39–79%, reduced receptor–ligand affinity by 41–82%, and attenuated MCH-stimulated intracellular Ca2+ release, confirming that MCHR2 protein level directly controls downstream Gαq-mediated Ca2+ signaling.\",\n      \"method\": \"shRNA knockdown, radioligand binding assay, intracellular Ca2+ assay, RT-PCR, western blot\",\n      \"journal\": \"Cellular and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple orthogonal readouts (binding, affinity, Ca2+ signaling) in a single lab\",\n      \"pmids\": [\"20937223\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MCHR2 is a human Gαq-coupled GPCR that binds melanin-concentrating hormone (MCH) with high affinity (Kd ~0.17–2.2 nM), activates phospholipase C to produce inositol phosphates and intracellular Ca2+ release, does not inhibit cAMP production, and is insensitive to pertussis toxin, distinguishing it mechanistically from the Gi/Go-coupled MCHR1; receptor expression level directly governs the magnitude of MCH-stimulated Ca2+ signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MCHR2 is a G protein-coupled receptor for melanin-concentrating hormone (MCH) that transduces ligand binding into Gαq-mediated intracellular signaling [#0]. It binds MCH with high affinity (Kd ~0.17–2.2 nM) and, upon activation, drives inositol phosphate turnover and intracellular Ca2+ release while leaving forskolin-stimulated cAMP production unaffected; its signaling is insensitive to pertussis toxin, establishing exclusive Gq coupling and distinguishing it mechanistically from the Gi/Go- and Gq-coupled MCHR1 [#0, #1]. The receptor discriminates ligand orthologs, with salmon MCH showing ~10-fold weaker potency than mammalian MCH at MCHR2 [#1], and this Gq-restricted profile is conserved in the rhesus ortholog [#2]. Receptor abundance directly governs signaling output: shRNA knockdown of MCHR2 proportionally reduces MCH binding, ligand affinity, and MCH-stimulated Ca2+ release [#5]. Two natural coding variants (R63K, R152Q) do not alter binding or signaling [#3]. Beyond ligand binding and proximal Gq/PLC/Ca2+ coupling, the physiological and tissue-level roles of MCHR2 have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that MCHR2 is a bona fide MCH receptor and defined its G protein coupling, resolving how it differs signally from the previously known MCHR1.\",\n      \"evidence\": \"Radioligand binding, inositol phosphate turnover, intracellular Ca2+ and cAMP assays with pertussis toxin treatment in mammalian and stable CHO cells, across two independent labs\",\n      \"pmids\": [\"11404457\", \"11459838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the structural basis of Gq selectivity\", \"Endogenous tissue context and physiological output not addressed\", \"Ligand ortholog selectivity at MCHR2 only partly mapped\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed MCHR2 distinguishes MCH orthologs pharmacologically, revealing receptor-specific ligand recognition not seen at MCHR1.\",\n      \"evidence\": \"Radioligand binding, Ca2+, IP and cAMP assays comparing salmon versus mammalian MCH potency in stable CHO cells\",\n      \"pmids\": [\"11459838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Residues governing ortholog discrimination not identified\", \"No structural model of the ligand-binding pocket\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated that the Gq-exclusive signaling mode is conserved across primates, supporting it as an intrinsic receptor property rather than a cell-context artifact.\",\n      \"evidence\": \"Radioligand binding (Kd 2.2 nM) and signaling assays of cloned rhesus MCH-R2 in expressing cells\",\n      \"pmids\": [\"12182940\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab characterization\", \"No comparison of downstream physiology between species\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Tested whether common coding variants alter receptor function, addressing a candidate-gene link to phenotypic variation.\",\n      \"evidence\": \"Site-directed mutagenesis of R63K and R152Q variants with binding, cAMP and Ca2+ assays in CHO cells\",\n      \"pmids\": [\"15340116\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Variants tested only in a heterologous system\", \"No in vivo or expression-level consequences assessed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided refined quantitative binding and signaling parameters for the human receptor, anchoring affinity and potency values.\",\n      \"evidence\": \"Radioligand binding (Kd 0.170 nM) and intracellular Ca2+ assay (EC50 2.32 nM) in stable CHO cells\",\n      \"pmids\": [\"20099459\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study, single lab\", \"No endogenous-cell measurements\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that receptor protein abundance is rate-limiting for downstream signaling, linking expression level directly to Gq/Ca2+ output magnitude.\",\n      \"evidence\": \"shRNA knockdown in CHO cells with RT-PCR, western blot, radioligand binding and Ca2+ assays\",\n      \"pmids\": [\"20937223\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Demonstrated only in an overexpression CHO system\", \"Does not address regulation of MCHR2 expression in native tissues\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The physiological roles, native tissue signaling, regulatory inputs, and structural basis of ligand recognition for MCHR2 remain undefined in the available corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No in vivo functional studies\", \"No structural data on ligand binding or Gq engagement\", \"Endogenous expression and downstream physiology 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]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}