{"gene":"PTH2R","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2016,"finding":"TIP39 (PTH2R endogenous ligand) binds PTH2R at the keratinocyte membrane to increase intracellular calcium and trigger terminal differentiation markers (decreased keratin-14, increased involucrin); PTH2R knockout mice show increased epidermal thickness, confirming a functional role in keratinocyte differentiation.","method":"Recombinant TIP39 addition to human keratinocytes, subcellular localization by immunofluorescence during calcium-induced differentiation, PTH2R(-/-) mouse phenotyping","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse phenotype plus ligand-stimulation assay with defined molecular readouts, single lab","pmids":["27000502"],"is_preprint":false},{"year":2011,"finding":"In zebrafish, hedgehog (Hh) signaling regulates pth2 transcript levels in the diencephalon; pth2r is broadly expressed in the CNS and otic vesicles, whereas pth2 is expressed in adjacent diencephalic cells and otic vesicles, establishing ligand-receptor co-expression and Hh-pathway control of pth2 in a vertebrate developmental context.","method":"Mutant analysis of hedgehog-pathway zebrafish mutants, in situ hybridization expression mapping, genomic/synteny analysis","journal":"The Journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic mutant epistasis with defined expression readout, single lab","pmids":["21880859"],"is_preprint":false},{"year":2025,"finding":"In dorsal CA1 hippocampal neurons, adenylyl cyclase 8 (Adcy8) maintains PTH2R protein levels via the MAPK signaling pathway; Adcy8 conditional knockout reduces PTH2R, decreasing neuronal excitability and glutamatergic neurotransmission, causing depressive-like behavior. PTH2R overexpression rescues these deficits, and chronic hippocampal infusion of TIP39 (endogenous PTH2R ligand) alleviates depressive-like behaviors in Adcy8 CKO mice.","method":"Conditional knockout (AAV-Cre), AAV-shRNA knockdown of Pth2r, PTH2R overexpression rescue, electrophysiology (neuronal excitability), glutamatergic neurotransmission assays, MAPK pathway analysis, chronic TIP39 infusion","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including KO, KD, overexpression rescue, pathway analysis, and pharmacological rescue in a single study","pmids":["41387170"],"is_preprint":false},{"year":2021,"finding":"A functional SNP (rs13383928) acts as an enhancer in lung cells (T allele shows higher enhancer activity by dual luciferase assay) and physically contacts the PTH2R promoter (chromosome conformation capture); transcription factor FOXJ2 binds this region (chromatin immunoprecipitation), linking the SNP to PTH2R transcriptional regulation in lung tissue.","method":"Dual luciferase enhancer assay, chromosome conformation capture (3C), chromatin immunoprecipitation (ChIP), linkage disequilibrium analysis","journal":"Human heredity","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal functional genomics methods in a single study establishing transcriptional regulatory mechanism","pmids":["33550301"],"is_preprint":false},{"year":2022,"finding":"Knockdown of PTH2R in ovarian cancer cells inhibits proliferation, invasion, and migration, demonstrating a functional role of PTH2R in tumor cell growth and motility.","method":"siRNA/shRNA knockdown, CCK-8 proliferation assay, Transwell invasion/migration assay, Western blot, qPCR","journal":"Cancer cell international","confidence":"Low","confidence_rationale":"Tier 3 — single lab, functional KD assays but no pathway placement or molecular mechanism identified","pmids":["35410353"],"is_preprint":false}],"current_model":"PTH2R is a class B GPCR activated by its endogenous ligand TIP39 (tuberoinfundibular peptide of 39 residues); in keratinocytes it transduces TIP39 binding into intracellular calcium elevation and terminal differentiation, while in hippocampal CA1 neurons its expression is maintained downstream of adenylyl cyclase 8 via MAPK signaling to sustain neuronal excitability and glutamatergic neurotransmission, and its transcription in lung tissue is controlled by an enhancer element bound by FOXJ2 and regulated by the SNP rs13383928."},"narrative":{"teleology":[{"year":2011,"claim":"Establishing that pth2 ligand expression in the vertebrate CNS is regulated by hedgehog signaling and that pth2r is broadly co-expressed in the brain and otic vesicles placed the TIP39–PTH2R axis within a developmental signaling hierarchy.","evidence":"Hedgehog-pathway zebrafish mutant analysis with in situ hybridization expression mapping","pmids":["21880859"],"confidence":"Medium","gaps":["Whether Hh regulation of PTH2 ligand is conserved in mammals is untested","Functional consequence of pth2r expression in otic vesicles is unknown","Downstream signaling pathway activated by Pth2r in the developing CNS was not examined"]},{"year":2016,"claim":"Demonstrating that TIP39 activates PTH2R at the keratinocyte membrane to elevate intracellular calcium and drive terminal differentiation—confirmed by epidermal thickening in PTH2R knockout mice—established a non-neuronal physiological function for this receptor.","evidence":"Recombinant TIP39 stimulation of human keratinocytes with calcium and differentiation marker readouts; PTH2R−/− mouse phenotyping","pmids":["27000502"],"confidence":"Medium","gaps":["Single-lab study; independent replication not available","The downstream signaling cascade between calcium elevation and involucrin induction was not mapped","Whether PTH2R signals through Gαs/cAMP or Gαq/calcium in keratinocytes was not dissected"]},{"year":2021,"claim":"Identifying an enhancer element (rs13383928) that physically contacts the PTH2R promoter and is bound by FOXJ2 revealed a transcriptional regulatory mechanism controlling PTH2R expression in lung tissue.","evidence":"Dual luciferase enhancer assay, chromosome conformation capture (3C), and ChIP in lung cells","pmids":["33550301"],"confidence":"Medium","gaps":["Functional consequence of altered PTH2R expression in lung physiology is unknown","Whether FOXJ2 regulation of PTH2R operates in other tissues was not tested","No knockout or knockdown of FOXJ2 was performed to confirm necessity"]},{"year":2025,"claim":"Revealing that adenylyl cyclase 8 sustains PTH2R protein levels via MAPK signaling in hippocampal CA1 neurons, and that PTH2R is required for neuronal excitability and glutamatergic neurotransmission, connected the receptor to mood regulation and provided a complete loss-of-function/rescue circuit.","evidence":"Conditional Adcy8 knockout, AAV-shRNA Pth2r knockdown, PTH2R overexpression rescue, electrophysiology, and chronic TIP39 hippocampal infusion in mice","pmids":["41387170"],"confidence":"High","gaps":["The specific MAPK pathway member(s) that regulate PTH2R transcription or stability are not identified","Whether PTH2R acts through Gαs-cAMP or alternative effectors in hippocampal neurons is unresolved","Relevance to human depression has not been demonstrated"]},{"year":null,"claim":"The intracellular signaling effectors (specific G-protein coupling, second messengers) directly activated by PTH2R in neurons and other tissues, and the structural basis of TIP39 selectivity for PTH2R over PTH1R, remain uncharacterized by direct experimental evidence.","evidence":"","pmids":[],"confidence":"High","gaps":["No G-protein coupling selectivity data from reconstituted systems","No structural model of the TIP39–PTH2R complex","Physiological roles in lung and inner ear implied by expression data but not functionally tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2]}],"complexes":[],"partners":["TIP39","ADCY8","FOXJ2"],"other_free_text":[]},"mechanistic_narrative":"PTH2R is a class B G protein-coupled receptor activated by its endogenous ligand TIP39 that transduces signals through intracellular calcium and cAMP/MAPK pathways to regulate cell differentiation, neuronal excitability, and glutamatergic neurotransmission. In keratinocytes, TIP39–PTH2R signaling elevates intracellular calcium and promotes terminal differentiation, with PTH2R knockout mice displaying increased epidermal thickness [PMID:27000502]. In hippocampal CA1 neurons, adenylyl cyclase 8 maintains PTH2R expression via the MAPK pathway; loss of PTH2R reduces neuronal excitability and glutamatergic transmission, producing depressive-like behavior that is rescued by PTH2R overexpression or chronic TIP39 infusion [PMID:41387170]."},"prefetch_data":{"uniprot":{"accession":"P49190","full_name":"Parathyroid hormone 2 receptor","aliases":[],"length_aa":550,"mass_kda":62.2,"function":"This is a specific receptor for parathyroid hormone. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. PTH2R may be responsible for PTH effects in a number of physiological systems. It may play a significant role in pancreatic function. PTH2R presence in neurons indicates that it may function as a neurotransmitter receptor (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P49190/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTH2R","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PTH2R","total_profiled":1310},"omim":[{"mim_id":"601469","title":"PARATHYROID HORMONE 2 RECEPTOR; PTH2R","url":"https://www.omim.org/entry/601469"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":4.1},{"tissue":"retina","ntpm":15.2}],"url":"https://www.proteinatlas.org/search/PTH2R"},"hgnc":{"alias_symbol":[],"prev_symbol":["PTHR2"]},"alphafold":{"accession":"P49190","domains":[{"cath_id":"4.10.1240.10","chopping":"41-122","consensus_level":"high","plddt":87.1596,"start":41,"end":122},{"cath_id":"1.20.1070.10","chopping":"131-214_231-423","consensus_level":"high","plddt":83.6361,"start":131,"end":423}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P49190","model_url":"https://alphafold.ebi.ac.uk/files/AF-P49190-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P49190-F1-predicted_aligned_error_v6.png","plddt_mean":71.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTH2R","jax_strain_url":"https://www.jax.org/strain/search?query=PTH2R"},"sequence":{"accession":"P49190","fasta_url":"https://rest.uniprot.org/uniprotkb/P49190.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P49190/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P49190"}},"corpus_meta":[{"pmid":"21880859","id":"PMC_21880859","title":"Evolution of the vertebrate pth2 (tip39) gene family and the regulation of PTH type 2 receptor (pth2r) and its endogenous ligand pth2 by hedgehog signaling in zebrafish development.","date":"2011","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/21880859","citation_count":25,"is_preprint":false},{"pmid":"18280230","id":"PMC_18280230","title":"Genetic variation in the PTH pathway and bone phenotypes in elderly women: evaluation of PTH, PTHLH, PTHR1 and PTHR2 genes.","date":"2007","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/18280230","citation_count":22,"is_preprint":false},{"pmid":"23159568","id":"PMC_23159568","title":"Non-proteinogenic amino acids in the pThr-2 position of a pentamer peptide that confer high binding affinity for the polo box domain (PBD) of polo-like kinase 1 (Plk1).","date":"2012","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/23159568","citation_count":22,"is_preprint":false},{"pmid":"27000502","id":"PMC_27000502","title":"The Parathyroid Hormone Second Receptor PTH2R and its Ligand Tuberoinfundibular Peptide of 39 Residues TIP39 Regulate Intracellular Calcium and Influence Keratinocyte Differentiation.","date":"2016","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/27000502","citation_count":21,"is_preprint":false},{"pmid":"25462297","id":"PMC_25462297","title":"PFOA and PFOS are associated with reduced expression of the parathyroid hormone 2 receptor (PTH2R) gene in women.","date":"2014","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/25462297","citation_count":15,"is_preprint":false},{"pmid":"35410353","id":"PMC_35410353","title":"PTH2R is related to cell proliferation and migration in ovarian cancer: a multi-omics analysis of bioinformatics and experiments.","date":"2022","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/35410353","citation_count":12,"is_preprint":false},{"pmid":"24378925","id":"PMC_24378925","title":"Variation in the PTH2R gene is associated with age-related degenerative changes in the lumbar spine.","date":"2013","source":"Journal of bone and mineral metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/24378925","citation_count":10,"is_preprint":false},{"pmid":"26044810","id":"PMC_26044810","title":"Breakpoint mapping by whole genome sequencing identifies PTH2R gene disruption in a patient with midline craniosynostosis and a de novo balanced chromosomal rearrangement.","date":"2015","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26044810","citation_count":7,"is_preprint":false},{"pmid":"33550301","id":"PMC_33550301","title":"Asbestos-Induced Lung Cancer-Associated SNP rs13383928 Regulates PTH2R Expression in Lung Tissue.","date":"2021","source":"Human heredity","url":"https://pubmed.ncbi.nlm.nih.gov/33550301","citation_count":3,"is_preprint":false},{"pmid":"39698573","id":"PMC_39698573","title":"Depletion of intrinsic renal macrophages with moderate-to-high expression of CD163, MRC1, PTH2R, PDE4D, and CUBN in regulating podocyte injury in diabetic nephropathy: a single-cell RNA sequencing analysis.","date":"2024","source":"Translational andrology and urology","url":"https://pubmed.ncbi.nlm.nih.gov/39698573","citation_count":3,"is_preprint":false},{"pmid":"34992382","id":"PMC_34992382","title":"Clinical Impact of Switching to Ceritinib After Severe AEs Related to Crizotinib/Alectinib in a Novel PTH2R-ALK Fusion Lung Adenocarcinoma: A Case Report.","date":"2021","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34992382","citation_count":2,"is_preprint":false},{"pmid":"41387170","id":"PMC_41387170","title":"Adenylyl Cyclase 8 in Dorsal CA1 Neurons Prevents Depressive-Like Behaviors by Maintaining Neuronal Excitability and Glutamatergic Neurotransmission Through TIP39-PTH2R Signaling.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41387170","citation_count":0,"is_preprint":false},{"pmid":"41751388","id":"PMC_41751388","title":"Identification and Functional Validation of PTH2R as a Therapeutic Target in Lung Adenocarcinoma.","date":"2026","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/41751388","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8004,"output_tokens":1369,"usd":0.022274},"stage2":{"model":"claude-opus-4-6","input_tokens":4586,"output_tokens":1491,"usd":0.090307},"total_usd":0.112581,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"TIP39 (PTH2R endogenous ligand) binds PTH2R at the keratinocyte membrane to increase intracellular calcium and trigger terminal differentiation markers (decreased keratin-14, increased involucrin); PTH2R knockout mice show increased epidermal thickness, confirming a functional role in keratinocyte differentiation.\",\n      \"method\": \"Recombinant TIP39 addition to human keratinocytes, subcellular localization by immunofluorescence during calcium-induced differentiation, PTH2R(-/-) mouse phenotyping\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse phenotype plus ligand-stimulation assay with defined molecular readouts, single lab\",\n      \"pmids\": [\"27000502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In zebrafish, hedgehog (Hh) signaling regulates pth2 transcript levels in the diencephalon; pth2r is broadly expressed in the CNS and otic vesicles, whereas pth2 is expressed in adjacent diencephalic cells and otic vesicles, establishing ligand-receptor co-expression and Hh-pathway control of pth2 in a vertebrate developmental context.\",\n      \"method\": \"Mutant analysis of hedgehog-pathway zebrafish mutants, in situ hybridization expression mapping, genomic/synteny analysis\",\n      \"journal\": \"The Journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic mutant epistasis with defined expression readout, single lab\",\n      \"pmids\": [\"21880859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In dorsal CA1 hippocampal neurons, adenylyl cyclase 8 (Adcy8) maintains PTH2R protein levels via the MAPK signaling pathway; Adcy8 conditional knockout reduces PTH2R, decreasing neuronal excitability and glutamatergic neurotransmission, causing depressive-like behavior. PTH2R overexpression rescues these deficits, and chronic hippocampal infusion of TIP39 (endogenous PTH2R ligand) alleviates depressive-like behaviors in Adcy8 CKO mice.\",\n      \"method\": \"Conditional knockout (AAV-Cre), AAV-shRNA knockdown of Pth2r, PTH2R overexpression rescue, electrophysiology (neuronal excitability), glutamatergic neurotransmission assays, MAPK pathway analysis, chronic TIP39 infusion\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including KO, KD, overexpression rescue, pathway analysis, and pharmacological rescue in a single study\",\n      \"pmids\": [\"41387170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A functional SNP (rs13383928) acts as an enhancer in lung cells (T allele shows higher enhancer activity by dual luciferase assay) and physically contacts the PTH2R promoter (chromosome conformation capture); transcription factor FOXJ2 binds this region (chromatin immunoprecipitation), linking the SNP to PTH2R transcriptional regulation in lung tissue.\",\n      \"method\": \"Dual luciferase enhancer assay, chromosome conformation capture (3C), chromatin immunoprecipitation (ChIP), linkage disequilibrium analysis\",\n      \"journal\": \"Human heredity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional genomics methods in a single study establishing transcriptional regulatory mechanism\",\n      \"pmids\": [\"33550301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Knockdown of PTH2R in ovarian cancer cells inhibits proliferation, invasion, and migration, demonstrating a functional role of PTH2R in tumor cell growth and motility.\",\n      \"method\": \"siRNA/shRNA knockdown, CCK-8 proliferation assay, Transwell invasion/migration assay, Western blot, qPCR\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, functional KD assays but no pathway placement or molecular mechanism identified\",\n      \"pmids\": [\"35410353\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTH2R is a class B GPCR activated by its endogenous ligand TIP39 (tuberoinfundibular peptide of 39 residues); in keratinocytes it transduces TIP39 binding into intracellular calcium elevation and terminal differentiation, while in hippocampal CA1 neurons its expression is maintained downstream of adenylyl cyclase 8 via MAPK signaling to sustain neuronal excitability and glutamatergic neurotransmission, and its transcription in lung tissue is controlled by an enhancer element bound by FOXJ2 and regulated by the SNP rs13383928.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PTH2R is a class B G protein-coupled receptor activated by its endogenous ligand TIP39 that transduces signals through intracellular calcium and cAMP/MAPK pathways to regulate cell differentiation, neuronal excitability, and glutamatergic neurotransmission. In keratinocytes, TIP39–PTH2R signaling elevates intracellular calcium and promotes terminal differentiation, with PTH2R knockout mice displaying increased epidermal thickness [PMID:27000502]. In hippocampal CA1 neurons, adenylyl cyclase 8 maintains PTH2R expression via the MAPK pathway; loss of PTH2R reduces neuronal excitability and glutamatergic transmission, producing depressive-like behavior that is rescued by PTH2R overexpression or chronic TIP39 infusion [PMID:41387170].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing that pth2 ligand expression in the vertebrate CNS is regulated by hedgehog signaling and that pth2r is broadly co-expressed in the brain and otic vesicles placed the TIP39–PTH2R axis within a developmental signaling hierarchy.\",\n      \"evidence\": \"Hedgehog-pathway zebrafish mutant analysis with in situ hybridization expression mapping\",\n      \"pmids\": [\"21880859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether Hh regulation of PTH2 ligand is conserved in mammals is untested\",\n        \"Functional consequence of pth2r expression in otic vesicles is unknown\",\n        \"Downstream signaling pathway activated by Pth2r in the developing CNS was not examined\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating that TIP39 activates PTH2R at the keratinocyte membrane to elevate intracellular calcium and drive terminal differentiation—confirmed by epidermal thickening in PTH2R knockout mice—established a non-neuronal physiological function for this receptor.\",\n      \"evidence\": \"Recombinant TIP39 stimulation of human keratinocytes with calcium and differentiation marker readouts; PTH2R−/− mouse phenotyping\",\n      \"pmids\": [\"27000502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; independent replication not available\",\n        \"The downstream signaling cascade between calcium elevation and involucrin induction was not mapped\",\n        \"Whether PTH2R signals through Gαs/cAMP or Gαq/calcium in keratinocytes was not dissected\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying an enhancer element (rs13383928) that physically contacts the PTH2R promoter and is bound by FOXJ2 revealed a transcriptional regulatory mechanism controlling PTH2R expression in lung tissue.\",\n      \"evidence\": \"Dual luciferase enhancer assay, chromosome conformation capture (3C), and ChIP in lung cells\",\n      \"pmids\": [\"33550301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of altered PTH2R expression in lung physiology is unknown\",\n        \"Whether FOXJ2 regulation of PTH2R operates in other tissues was not tested\",\n        \"No knockout or knockdown of FOXJ2 was performed to confirm necessity\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealing that adenylyl cyclase 8 sustains PTH2R protein levels via MAPK signaling in hippocampal CA1 neurons, and that PTH2R is required for neuronal excitability and glutamatergic neurotransmission, connected the receptor to mood regulation and provided a complete loss-of-function/rescue circuit.\",\n      \"evidence\": \"Conditional Adcy8 knockout, AAV-shRNA Pth2r knockdown, PTH2R overexpression rescue, electrophysiology, and chronic TIP39 hippocampal infusion in mice\",\n      \"pmids\": [\"41387170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The specific MAPK pathway member(s) that regulate PTH2R transcription or stability are not identified\",\n        \"Whether PTH2R acts through Gαs-cAMP or alternative effectors in hippocampal neurons is unresolved\",\n        \"Relevance to human depression has not been demonstrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intracellular signaling effectors (specific G-protein coupling, second messengers) directly activated by PTH2R in neurons and other tissues, and the structural basis of TIP39 selectivity for PTH2R over PTH1R, remain uncharacterized by direct experimental evidence.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No G-protein coupling selectivity data from reconstituted systems\",\n        \"No structural model of the TIP39–PTH2R complex\",\n        \"Physiological roles in lung and inner ear implied by expression data but not functionally tested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TIP39\",\n      \"ADCY8\",\n      \"FOXJ2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}