{"gene":"PROKR1","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2006,"finding":"PKR1 (prokineticin receptor 1) mediates nociceptor activation and sensitization through pharmacological interaction with TRPV1; pkr1-null mice show impaired responsiveness to noxious heat, mechanical stimuli, capsaicin, and protons, and Bv8-responsive neurons from pkr1-null mice show reduced Ca2+ responses to capsaicin, establishing PKR1 as required for TRPV1-dependent nociceptor sensitization","method":"pkr1 knockout mice, Ca2+ imaging of DRG neurons, behavioral nociception assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular and behavioral phenotype, replicated with multiple orthogonal methods","pmids":["16793879"],"is_preprint":false},{"year":2007,"finding":"PKR1 signaling activates Akt in cardiomyocytes to promote survival against oxidative stress, and promotes vessel-like formation in cardiac endothelial cells independently of VEGF; siRNA knockdown of PKR1 completely reverses prokineticin-2-induced survival and angiogenesis effects","method":"PKR1 overexpression, siRNA knockdown, in vitro angiogenesis assay, in vivo myocardial infarction gene transfer model","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (OE, KD, in vivo rescue) in single study with defined molecular readouts","pmids":["17442730"],"is_preprint":false},{"year":2009,"finding":"PROK1-PROKR1 signaling induces IL-11 expression via a Gq/11-ERK-Ca2+-calcineurin-NFAT pathway; RCAN1-4 acts as a negative regulator of this calcineurin-mediated signaling; lentiviral miRNA knockdown of PROK1 reduces IL-11 expression in human decidua","method":"PROKR1-expressing Ishikawa cells, Ca2+ signaling inhibitors, adenoviral RCAN1-4 overexpression, lentiviral miRNA knockdown, first trimester decidua explants","journal":"Molecular human reproduction","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal pharmacological and genetic interventions with defined signaling pathway","pmids":["19801577"],"is_preprint":false},{"year":2011,"finding":"PKR1 gain- and loss-of-function studies in mouse heart show PKR1 upregulates its own ligand PK2 in a paracrine loop, and PKR1 in epicardin-positive progenitor cells from kidney mediates PK2-induced differentiation into endothelial and smooth muscle cells","method":"Transgenic mice overexpressing PKR1, loss-of-function mouse models, epicardin-positive progenitor cell isolation and differentiation assays","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 — genetic gain/loss of function with cellular differentiation readout, review summarizing primary data","pmids":["21856786"],"is_preprint":false},{"year":2013,"finding":"PROKR1 variant I379V decreases intracellular calcium influx but increases cell invasiveness compared to wild-type receptor when expressed in HEK293 and JAR cells, revealing that this residue influences both calcium signaling and cell invasion downstream of PROKR1","method":"Ectopic expression of variant in HEK293 and JAR cells, intracellular calcium influx assay, invasion assay","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 — functional variant characterization with multiple cellular readouts in a single study","pmids":["23687280"],"is_preprint":false},{"year":2018,"finding":"PK2β, a splice variant-derived ligand, preferentially binds PKR1 over PKR2 and activates a signaling cascade independent of Gαi/o coupling; the PKR1 amino-terminal region is important for PK2β binding specificity as shown by PKR1 mutant analysis and GST pull-down; PK2β does not induce STAT3 phosphorylation in DRG explants unlike PK2","method":"Yeast GPCR coupling assay with PKR mutants, GST pull-down, in vivo nociception assays, organotypic DRG explant signaling","journal":"Neuropeptides","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (yeast system, pull-down, in vivo) in single study","pmids":["30253862"],"is_preprint":false},{"year":2024,"finding":"PROKR1 signals via Gs-mediated cAMP-CREB phosphorylation to upregulate NR4A2, promoting oxidative muscle fiber specification and mitochondrial biogenesis; Prokr1-deficient mice show reduced oxidative fiber composition, impaired glucose and insulin tolerance, and reduced energy expenditure, all rescued by AAV-mediated Prokr1 reintroduction","method":"ChIP-PCR, luciferase reporter assay, pharmacological inhibitors, Prokr1 knockout mice, AAV rescue, myotube differentiation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including ChIP, reporter assay, KO with in vivo rescue, defining full signaling axis","pmids":["38232288"],"is_preprint":false},{"year":2025,"finding":"Celecoxib acts as a PROKR1 agonist by selectively activating Gs signaling (EC50 ~4 μM), competitively inhibiting PK2 binding to PROKR1, and increasing pCREB and NR4A2 levels, thereby promoting oxidative muscle fiber formation and improving metabolic function in mice","method":"Molecular docking, competitive binding assay, PROKR1 signaling assays in overexpressing cells, murine and human myotube assays, in vivo offspring dietary exposure model","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"Medium","confidence_rationale":"Tier 2 — competitive binding assay plus signaling and in vivo functional readouts in a single study","pmids":["39887895"],"is_preprint":false},{"year":2026,"finding":"PKR1 in epicardial Tcf21+ cells controls epithelial-to-mesenchymal transition by suppressing miR-124, which directly targets the 3' UTR of SNAI2; loss of PKR1 in epicardial cells upregulates miR-124, suppresses SNAI2, causes failed EMT and apoptosis; miR-124 inhibition or PKR1 reintroduction restores SNAI2 and EMT, and epicardial-derived miR-124 paracrinally suppresses cardiomyocyte contractility","method":"Conditional epicardial-specific Tcf21-PKR1 knockout mice, transcriptomics, 3'UTR reporter assay (implied by direct targeting statement), miR-124 inhibition rescue, PKR1 reintroduction, conditioned media/ex vivo paracrine assays","journal":"Stem cells (Dayton, Ohio)","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with in vivo phenotype, molecular rescue experiments, and paracrine functional validation across multiple orthogonal approaches","pmids":["41460181"],"is_preprint":false},{"year":2026,"finding":"IS39, a non-peptide PKR1 agonist, reduces reactive oxygen species, suppresses profibrotic gene expression, and protects cardiomyocytes from doxorubicin-induced cytotoxicity via PKR1; these effects are abolished by PKR1 knockdown or antagonism, confirming on-target cardioprotective signaling","method":"In vitro primary cardiomyocyte assays, PKR1 knockdown and antagonism, in vivo murine doxorubicin cardiotoxicity model, cardiac function/histopathology endpoints","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — on-target confirmation by KD and antagonism with multiple functional readouts in single study","pmids":["41860378"],"is_preprint":false},{"year":2025,"finding":"PKR1 agonist IS20 induces GDNF gene expression and protein secretion in astrocytes, and systemic IS20 administration elevates GDNF levels in mouse brain nigrostriatal system, providing neuroprotection in MPTP and MitoPark PD models","method":"Cultured astrocyte treatment with PK2 protein/gene/PKR1 agonist IS20, in vivo MPTP and MitoPark mouse models, brain GDNF measurement","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multiple in vitro and in vivo approaches, but preprint not yet peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"PROKR1 is a G protein-coupled receptor that signals via Gq/11-Ca2+-calcineurin-NFAT and Gs-cAMP-CREB axes to regulate diverse biological processes including nociceptor sensitization through interaction with TRPV1, cardiomyocyte survival via Akt activation, epicardial EMT through a PKR1-miR-124-SNAI2 axis, oxidative muscle fiber specification via CREB-NR4A2, and astrocytic GDNF induction for neuroprotection; its splice-variant ligand PK2β preferentially engages PKR1 through its N-terminal domain in a Gαi/o-independent manner, and the I379V variant alters calcium signaling and cell invasiveness."},"narrative":{"teleology":[{"year":2006,"claim":"Establishing PKR1 as required for nociceptor function resolved whether prokineticin receptors contribute to pain processing and identified a functional partnership with TRPV1 at the sensory neuron level.","evidence":"pkr1-knockout mice with behavioral nociception assays and Ca²⁺ imaging of DRG neurons","pmids":["16793879"],"confidence":"High","gaps":["Mechanism of physical or functional coupling between PKR1 and TRPV1 not defined","Whether PKR1-TRPV1 interaction is direct or requires intermediate kinases unknown","Contribution of PKR2 to the same nociceptive modalities not excluded"]},{"year":2007,"claim":"Demonstrating that PKR1 activates Akt for cardiomyocyte survival and promotes VEGF-independent vessel formation established a cardioprotective role distinct from classical angiogenic pathways.","evidence":"PKR1 overexpression and siRNA knockdown in cardiomyocytes and endothelial cells, in vivo myocardial infarction gene transfer","pmids":["17442730"],"confidence":"High","gaps":["G protein coupling specificity for Akt activation in cardiomyocytes not determined","Direct targets downstream of Akt in this context not identified"]},{"year":2009,"claim":"Mapping the PROKR1→Gq/11→ERK→Ca²⁺→calcineurin→NFAT cascade for IL-11 induction defined the first complete intracellular signaling pathway downstream of this receptor and identified RCAN1-4 as its endogenous brake.","evidence":"Pharmacological inhibitor panel, adenoviral RCAN1-4 overexpression, and lentiviral PROK1 knockdown in Ishikawa cells and decidual explants","pmids":["19801577"],"confidence":"High","gaps":["Whether this Gq/11-NFAT axis operates in non-reproductive tissues not tested","Physiological consequence of IL-11 induction for implantation not shown in vivo"]},{"year":2011,"claim":"Gain- and loss-of-function studies revealing a PK2–PKR1 paracrine loop and PKR1-dependent differentiation of epicardin⁺ progenitors into vascular lineages extended the cardiac role from survival to progenitor cell specification.","evidence":"Transgenic PKR1 overexpression/loss-of-function mice, epicardin⁺ progenitor cell differentiation assays","pmids":["21856786"],"confidence":"Medium","gaps":["Signaling intermediates linking PKR1 to progenitor differentiation not defined","Whether PKR1 is sufficient or merely necessary for vascular lineage commitment in vivo not resolved","Data reported as review summary of primary studies"]},{"year":2013,"claim":"Functional characterization of the I379V variant showed that a single residue in PROKR1 uncouples calcium signaling from cell invasion, revealing that distinct downstream effector arms can be independently modulated.","evidence":"Ectopic expression of wild-type and I379V PROKR1 in HEK293 and JAR cells with calcium and invasion assays","pmids":["23687280"],"confidence":"Medium","gaps":["Structural basis for how I379V alters effector coupling not determined","Clinical significance of this variant not established in patient cohorts","Whether the invasiveness phenotype operates through a specific G protein arm unknown"]},{"year":2018,"claim":"Identifying PK2β as a splice-variant ligand that selectively engages PKR1 via its N-terminal domain independently of Gαi/o coupling established ligand-biased signaling at this receptor.","evidence":"Yeast GPCR coupling assay with PKR1/PKR2 mutants, GST pull-down, in vivo nociception, DRG explant signaling","pmids":["30253862"],"confidence":"Medium","gaps":["Which G protein(s) PK2β does couple through at PKR1 not fully defined","Physiological contexts where PK2β versus PK2 selectivity is relevant remain unclear","Structural basis for N-terminal domain selectivity not resolved"]},{"year":2024,"claim":"Defining a complete Gs–cAMP–CREB–NR4A2 axis by which PKR1 specifies oxidative muscle fibers and mitochondrial biogenesis, with full in vivo KO-rescue validation, established a metabolic function for PKR1 beyond the cardiovascular and nociceptive systems.","evidence":"ChIP-PCR, luciferase reporter, pharmacological inhibitors, Prokr1-KO mice with AAV rescue, myotube differentiation assays","pmids":["38232288"],"confidence":"High","gaps":["Whether PKR1 acts cell-autonomously in muscle fibers or also through paracrine mechanisms not fully resolved","Upstream regulation of PKR1 expression in skeletal muscle not characterized"]},{"year":2025,"claim":"Identifying celecoxib as a selective Gs-biased PROKR1 agonist that competes with PK2 binding and phenocopies PKR1-mediated oxidative fiber formation provided pharmacological validation of the Gs–CREB–NR4A2 muscle axis.","evidence":"Molecular docking, competitive binding assay, PROKR1 signaling in overexpressing cells, murine and human myotube assays, in vivo dietary exposure model","pmids":["39887895"],"confidence":"Medium","gaps":["Off-target effects of celecoxib via COX-2 inhibition not fully excluded in muscle phenotype","Whether celecoxib binds the orthosteric or allosteric pocket on PKR1 not structurally confirmed"]},{"year":2026,"claim":"Conditional deletion of PKR1 in Tcf21⁺ epicardial cells revealed a PKR1→miR-124⊣SNAI2 axis controlling epicardial EMT and demonstrated that epicardial-derived miR-124 paracrinally suppresses cardiomyocyte contractility, linking PKR1 to intercellular communication in heart development.","evidence":"Conditional epicardial Tcf21-PKR1 knockout mice, transcriptomics, 3′UTR reporter, miR-124 inhibition rescue, conditioned media paracrine assays","pmids":["41460181"],"confidence":"High","gaps":["Direct transcriptional mechanism by which PKR1 suppresses miR-124 not identified","Whether this axis operates in adult cardiac repair or only in development not tested"]},{"year":2026,"claim":"Demonstrating that the non-peptide PKR1 agonist IS39 protects cardiomyocytes from doxorubicin toxicity via ROS reduction and antifibrotic signaling, abolished by PKR1 knockdown, confirmed druggability of the receptor's cardioprotective arm.","evidence":"Primary cardiomyocyte assays with PKR1 knockdown/antagonism, in vivo murine doxorubicin cardiotoxicity model","pmids":["41860378"],"confidence":"Medium","gaps":["Downstream signaling pathway (Akt, CREB, or other) mediating IS39 cardioprotection not mapped","Long-term safety and receptor selectivity of IS39 in vivo not established"]},{"year":null,"claim":"A high-resolution structure of PROKR1 in complex with its ligands or G proteins has not been reported, leaving the structural basis for biased signaling, ligand selectivity between PK2 and PK2β, and the mechanism of variant effects (e.g., I379V) unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No cryo-EM or crystal structure of PROKR1 available","Mechanism by which PKR1 couples to both Gq/11 and Gs in different tissues not structurally explained","Full interactome of PROKR1 beyond G proteins not systematically defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,5,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,4,5]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,8]}],"complexes":[],"partners":["TRPV1","PROK2","NR4A2","SNAI2","RCAN1"],"other_free_text":[]},"mechanistic_narrative":"PROKR1 (prokineticin receptor 1/PKR1) is a G protein-coupled receptor that transduces prokineticin ligand signals through multiple heterotrimeric G protein pathways to regulate nociception, cardiac homeostasis, and skeletal muscle metabolism. PKR1 couples to Gq/11 to activate ERK-Ca²⁺-calcineurin-NFAT signaling (driving IL-11 induction in decidual cells) and to Gs to stimulate cAMP-CREB-dependent transcription of NR4A2, which specifies oxidative muscle fiber identity and mitochondrial biogenesis; Prokr1-deficient mice exhibit impaired glucose tolerance, reduced energy expenditure, and decreased oxidative fiber composition, all rescued by AAV-mediated receptor reintroduction [PMID:38232288, PMID:19801577]. In sensory neurons, PKR1 is required for TRPV1-dependent nociceptor sensitization to heat, capsaicin, and protons, as demonstrated by impaired pain responses and reduced capsaicin-evoked Ca²⁺ transients in pkr1-null mice [PMID:16793879]. In the heart, PKR1 activates Akt to promote cardiomyocyte survival under oxidative stress, drives epicardial epithelial-to-mesenchymal transition through a miR-124–SNAI2 axis in Tcf21⁺ progenitor cells, and mediates VEGF-independent angiogenesis in cardiac endothelial cells [PMID:17442730, PMID:41460181]."},"prefetch_data":{"uniprot":{"accession":"Q8TCW9","full_name":"Prokineticin receptor 1","aliases":["G-protein coupled receptor 73","G-protein coupled receptor ZAQ","GPR73a"],"length_aa":393,"mass_kda":44.8,"function":"Receptor for prokineticin 1. Exclusively coupled to the G(q) subclass of heteromeric G proteins. Activation leads to mobilization of calcium, stimulation of phosphoinositide turnover and activation of p44/p42 mitogen-activated protein kinase. May play a role during early pregnancy","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8TCW9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PROKR1","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/PROKR1","total_profiled":1310},"omim":[{"mim_id":"607123","title":"PROKINETICIN RECEPTOR 2; PROKR2","url":"https://www.omim.org/entry/607123"},{"mim_id":"607122","title":"PROKINETICIN RECEPTOR 1; PROKR1","url":"https://www.omim.org/entry/607122"},{"mim_id":"607002","title":"PROKINETICIN 2; PROK2","url":"https://www.omim.org/entry/607002"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"adipose tissue","ntpm":1.5},{"tissue":"adrenal gland","ntpm":1.0},{"tissue":"epididymis","ntpm":3.3}],"url":"https://www.proteinatlas.org/search/PROKR1"},"hgnc":{"alias_symbol":["PKR1","ZAQ","GPR73a"],"prev_symbol":["GPR73"]},"alphafold":{"accession":"Q8TCW9","domains":[{"cath_id":"1.20.1070.10","chopping":"37-42_55-358","consensus_level":"high","plddt":88.21,"start":37,"end":358}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TCW9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TCW9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TCW9-F1-predicted_aligned_error_v6.png","plddt_mean":77.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PROKR1","jax_strain_url":"https://www.jax.org/strain/search?query=PROKR1"},"sequence":{"accession":"Q8TCW9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TCW9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TCW9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TCW9"}},"corpus_meta":[{"pmid":"16793879","id":"PMC_16793879","title":"Impaired nociception and inflammatory pain sensation in mice lacking the prokineticin receptor PKR1: focus on interaction between PKR1 and the capsaicin receptor TRPV1 in pain behavior.","date":"2006","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16793879","citation_count":120,"is_preprint":false},{"pmid":"17442730","id":"PMC_17442730","title":"The prokineticin receptor-1 (GPR73) promotes cardiomyocyte survival and angiogenesis.","date":"2007","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/17442730","citation_count":79,"is_preprint":false},{"pmid":"17531315","id":"PMC_17531315","title":"Placental expression of EG-VEGF and its receptors PKR1 (prokineticin receptor-1) and PKR2 throughout mouse 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Science. B","url":"https://pubmed.ncbi.nlm.nih.gov/26984842","citation_count":5,"is_preprint":false},{"pmid":"38232288","id":"PMC_38232288","title":"PROKR1-CREB-NR4A2 axis for oxidative muscle fiber specification and improvement of metabolic function.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/38232288","citation_count":4,"is_preprint":false},{"pmid":"39825958","id":"PMC_39825958","title":"Gallic acid mitigates lipopolysaccharide-induced testicular inflammation via regulation of the NF-κB and PK2/PKR1 pathway.","date":"2025","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/39825958","citation_count":2,"is_preprint":false},{"pmid":"39887895","id":"PMC_39887895","title":"Celecoxib Enhances Oxidative Muscle Fibre Formation and Improves Muscle Functions Through Prokr1 Activation in Mice.","date":"2025","source":"Journal of cachexia, sarcopenia and muscle","url":"https://pubmed.ncbi.nlm.nih.gov/39887895","citation_count":1,"is_preprint":false},{"pmid":"41460181","id":"PMC_41460181","title":"miR-124 orchestrates epicardial-mesenchymal transformation and paracrine cardiomyocyte maturation in epicardial-specific Tcf21-PKR1 knockout mice.","date":"2026","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/41460181","citation_count":0,"is_preprint":false},{"pmid":"41860378","id":"PMC_41860378","title":"Second-generation prokineticin PKR1 receptor agonists: Advancing cardioprotection against chemotherapy-induced toxicity.","date":"2026","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41860378","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.18.25338283","title":"The Prokineticin System Is Downregulated in Idiopathic Rapid Eye Movement Sleep Behavior Disorder: Evidence from Olfactory Neurons","date":"2025-10-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.18.25338283","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.08.674934","title":"Prokineticin-2 Upregulates GDNF in Astrocytes and Pharmacological Modulation of PK2 Receptors offers Neuroprotection in Experimental Models of Parkinson’s Disease","date":"2025-09-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.08.674934","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16284,"output_tokens":2814,"usd":0.045531},"stage2":{"model":"claude-opus-4-6","input_tokens":6161,"output_tokens":2966,"usd":0.157433},"total_usd":0.202964,"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\": 2006,\n      \"finding\": \"PKR1 (prokineticin receptor 1) mediates nociceptor activation and sensitization through pharmacological interaction with TRPV1; pkr1-null mice show impaired responsiveness to noxious heat, mechanical stimuli, capsaicin, and protons, and Bv8-responsive neurons from pkr1-null mice show reduced Ca2+ responses to capsaicin, establishing PKR1 as required for TRPV1-dependent nociceptor sensitization\",\n      \"method\": \"pkr1 knockout mice, Ca2+ imaging of DRG neurons, behavioral nociception assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular and behavioral phenotype, replicated with multiple orthogonal methods\",\n      \"pmids\": [\"16793879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PKR1 signaling activates Akt in cardiomyocytes to promote survival against oxidative stress, and promotes vessel-like formation in cardiac endothelial cells independently of VEGF; siRNA knockdown of PKR1 completely reverses prokineticin-2-induced survival and angiogenesis effects\",\n      \"method\": \"PKR1 overexpression, siRNA knockdown, in vitro angiogenesis assay, in vivo myocardial infarction gene transfer model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (OE, KD, in vivo rescue) in single study with defined molecular readouts\",\n      \"pmids\": [\"17442730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PROK1-PROKR1 signaling induces IL-11 expression via a Gq/11-ERK-Ca2+-calcineurin-NFAT pathway; RCAN1-4 acts as a negative regulator of this calcineurin-mediated signaling; lentiviral miRNA knockdown of PROK1 reduces IL-11 expression in human decidua\",\n      \"method\": \"PROKR1-expressing Ishikawa cells, Ca2+ signaling inhibitors, adenoviral RCAN1-4 overexpression, lentiviral miRNA knockdown, first trimester decidua explants\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal pharmacological and genetic interventions with defined signaling pathway\",\n      \"pmids\": [\"19801577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PKR1 gain- and loss-of-function studies in mouse heart show PKR1 upregulates its own ligand PK2 in a paracrine loop, and PKR1 in epicardin-positive progenitor cells from kidney mediates PK2-induced differentiation into endothelial and smooth muscle cells\",\n      \"method\": \"Transgenic mice overexpressing PKR1, loss-of-function mouse models, epicardin-positive progenitor cell isolation and differentiation assays\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic gain/loss of function with cellular differentiation readout, review summarizing primary data\",\n      \"pmids\": [\"21856786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PROKR1 variant I379V decreases intracellular calcium influx but increases cell invasiveness compared to wild-type receptor when expressed in HEK293 and JAR cells, revealing that this residue influences both calcium signaling and cell invasion downstream of PROKR1\",\n      \"method\": \"Ectopic expression of variant in HEK293 and JAR cells, intracellular calcium influx assay, invasion assay\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional variant characterization with multiple cellular readouts in a single study\",\n      \"pmids\": [\"23687280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PK2β, a splice variant-derived ligand, preferentially binds PKR1 over PKR2 and activates a signaling cascade independent of Gαi/o coupling; the PKR1 amino-terminal region is important for PK2β binding specificity as shown by PKR1 mutant analysis and GST pull-down; PK2β does not induce STAT3 phosphorylation in DRG explants unlike PK2\",\n      \"method\": \"Yeast GPCR coupling assay with PKR mutants, GST pull-down, in vivo nociception assays, organotypic DRG explant signaling\",\n      \"journal\": \"Neuropeptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (yeast system, pull-down, in vivo) in single study\",\n      \"pmids\": [\"30253862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PROKR1 signals via Gs-mediated cAMP-CREB phosphorylation to upregulate NR4A2, promoting oxidative muscle fiber specification and mitochondrial biogenesis; Prokr1-deficient mice show reduced oxidative fiber composition, impaired glucose and insulin tolerance, and reduced energy expenditure, all rescued by AAV-mediated Prokr1 reintroduction\",\n      \"method\": \"ChIP-PCR, luciferase reporter assay, pharmacological inhibitors, Prokr1 knockout mice, AAV rescue, myotube differentiation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including ChIP, reporter assay, KO with in vivo rescue, defining full signaling axis\",\n      \"pmids\": [\"38232288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Celecoxib acts as a PROKR1 agonist by selectively activating Gs signaling (EC50 ~4 μM), competitively inhibiting PK2 binding to PROKR1, and increasing pCREB and NR4A2 levels, thereby promoting oxidative muscle fiber formation and improving metabolic function in mice\",\n      \"method\": \"Molecular docking, competitive binding assay, PROKR1 signaling assays in overexpressing cells, murine and human myotube assays, in vivo offspring dietary exposure model\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — competitive binding assay plus signaling and in vivo functional readouts in a single study\",\n      \"pmids\": [\"39887895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PKR1 in epicardial Tcf21+ cells controls epithelial-to-mesenchymal transition by suppressing miR-124, which directly targets the 3' UTR of SNAI2; loss of PKR1 in epicardial cells upregulates miR-124, suppresses SNAI2, causes failed EMT and apoptosis; miR-124 inhibition or PKR1 reintroduction restores SNAI2 and EMT, and epicardial-derived miR-124 paracrinally suppresses cardiomyocyte contractility\",\n      \"method\": \"Conditional epicardial-specific Tcf21-PKR1 knockout mice, transcriptomics, 3'UTR reporter assay (implied by direct targeting statement), miR-124 inhibition rescue, PKR1 reintroduction, conditioned media/ex vivo paracrine assays\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with in vivo phenotype, molecular rescue experiments, and paracrine functional validation across multiple orthogonal approaches\",\n      \"pmids\": [\"41460181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"IS39, a non-peptide PKR1 agonist, reduces reactive oxygen species, suppresses profibrotic gene expression, and protects cardiomyocytes from doxorubicin-induced cytotoxicity via PKR1; these effects are abolished by PKR1 knockdown or antagonism, confirming on-target cardioprotective signaling\",\n      \"method\": \"In vitro primary cardiomyocyte assays, PKR1 knockdown and antagonism, in vivo murine doxorubicin cardiotoxicity model, cardiac function/histopathology endpoints\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — on-target confirmation by KD and antagonism with multiple functional readouts in single study\",\n      \"pmids\": [\"41860378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PKR1 agonist IS20 induces GDNF gene expression and protein secretion in astrocytes, and systemic IS20 administration elevates GDNF levels in mouse brain nigrostriatal system, providing neuroprotection in MPTP and MitoPark PD models\",\n      \"method\": \"Cultured astrocyte treatment with PK2 protein/gene/PKR1 agonist IS20, in vivo MPTP and MitoPark mouse models, brain GDNF measurement\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro and in vivo approaches, but preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PROKR1 is a G protein-coupled receptor that signals via Gq/11-Ca2+-calcineurin-NFAT and Gs-cAMP-CREB axes to regulate diverse biological processes including nociceptor sensitization through interaction with TRPV1, cardiomyocyte survival via Akt activation, epicardial EMT through a PKR1-miR-124-SNAI2 axis, oxidative muscle fiber specification via CREB-NR4A2, and astrocytic GDNF induction for neuroprotection; its splice-variant ligand PK2β preferentially engages PKR1 through its N-terminal domain in a Gαi/o-independent manner, and the I379V variant alters calcium signaling and cell invasiveness.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PROKR1 (prokineticin receptor 1/PKR1) is a G protein-coupled receptor that transduces prokineticin ligand signals through multiple heterotrimeric G protein pathways to regulate nociception, cardiac homeostasis, and skeletal muscle metabolism. PKR1 couples to Gq/11 to activate ERK-Ca²⁺-calcineurin-NFAT signaling (driving IL-11 induction in decidual cells) and to Gs to stimulate cAMP-CREB-dependent transcription of NR4A2, which specifies oxidative muscle fiber identity and mitochondrial biogenesis; Prokr1-deficient mice exhibit impaired glucose tolerance, reduced energy expenditure, and decreased oxidative fiber composition, all rescued by AAV-mediated receptor reintroduction [PMID:38232288, PMID:19801577]. In sensory neurons, PKR1 is required for TRPV1-dependent nociceptor sensitization to heat, capsaicin, and protons, as demonstrated by impaired pain responses and reduced capsaicin-evoked Ca²⁺ transients in pkr1-null mice [PMID:16793879]. In the heart, PKR1 activates Akt to promote cardiomyocyte survival under oxidative stress, drives epicardial epithelial-to-mesenchymal transition through a miR-124–SNAI2 axis in Tcf21⁺ progenitor cells, and mediates VEGF-independent angiogenesis in cardiac endothelial cells [PMID:17442730, PMID:41460181].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing PKR1 as required for nociceptor function resolved whether prokineticin receptors contribute to pain processing and identified a functional partnership with TRPV1 at the sensory neuron level.\",\n      \"evidence\": \"pkr1-knockout mice with behavioral nociception assays and Ca²⁺ imaging of DRG neurons\",\n      \"pmids\": [\"16793879\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism of physical or functional coupling between PKR1 and TRPV1 not defined\",\n        \"Whether PKR1-TRPV1 interaction is direct or requires intermediate kinases unknown\",\n        \"Contribution of PKR2 to the same nociceptive modalities not excluded\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that PKR1 activates Akt for cardiomyocyte survival and promotes VEGF-independent vessel formation established a cardioprotective role distinct from classical angiogenic pathways.\",\n      \"evidence\": \"PKR1 overexpression and siRNA knockdown in cardiomyocytes and endothelial cells, in vivo myocardial infarction gene transfer\",\n      \"pmids\": [\"17442730\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"G protein coupling specificity for Akt activation in cardiomyocytes not determined\",\n        \"Direct targets downstream of Akt in this context not identified\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapping the PROKR1→Gq/11→ERK→Ca²⁺→calcineurin→NFAT cascade for IL-11 induction defined the first complete intracellular signaling pathway downstream of this receptor and identified RCAN1-4 as its endogenous brake.\",\n      \"evidence\": \"Pharmacological inhibitor panel, adenoviral RCAN1-4 overexpression, and lentiviral PROK1 knockdown in Ishikawa cells and decidual explants\",\n      \"pmids\": [\"19801577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether this Gq/11-NFAT axis operates in non-reproductive tissues not tested\",\n        \"Physiological consequence of IL-11 induction for implantation not shown in vivo\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Gain- and loss-of-function studies revealing a PK2–PKR1 paracrine loop and PKR1-dependent differentiation of epicardin⁺ progenitors into vascular lineages extended the cardiac role from survival to progenitor cell specification.\",\n      \"evidence\": \"Transgenic PKR1 overexpression/loss-of-function mice, epicardin⁺ progenitor cell differentiation assays\",\n      \"pmids\": [\"21856786\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Signaling intermediates linking PKR1 to progenitor differentiation not defined\",\n        \"Whether PKR1 is sufficient or merely necessary for vascular lineage commitment in vivo not resolved\",\n        \"Data reported as review summary of primary studies\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Functional characterization of the I379V variant showed that a single residue in PROKR1 uncouples calcium signaling from cell invasion, revealing that distinct downstream effector arms can be independently modulated.\",\n      \"evidence\": \"Ectopic expression of wild-type and I379V PROKR1 in HEK293 and JAR cells with calcium and invasion assays\",\n      \"pmids\": [\"23687280\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis for how I379V alters effector coupling not determined\",\n        \"Clinical significance of this variant not established in patient cohorts\",\n        \"Whether the invasiveness phenotype operates through a specific G protein arm unknown\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying PK2β as a splice-variant ligand that selectively engages PKR1 via its N-terminal domain independently of Gαi/o coupling established ligand-biased signaling at this receptor.\",\n      \"evidence\": \"Yeast GPCR coupling assay with PKR1/PKR2 mutants, GST pull-down, in vivo nociception, DRG explant signaling\",\n      \"pmids\": [\"30253862\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Which G protein(s) PK2β does couple through at PKR1 not fully defined\",\n        \"Physiological contexts where PK2β versus PK2 selectivity is relevant remain unclear\",\n        \"Structural basis for N-terminal domain selectivity not resolved\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defining a complete Gs–cAMP–CREB–NR4A2 axis by which PKR1 specifies oxidative muscle fibers and mitochondrial biogenesis, with full in vivo KO-rescue validation, established a metabolic function for PKR1 beyond the cardiovascular and nociceptive systems.\",\n      \"evidence\": \"ChIP-PCR, luciferase reporter, pharmacological inhibitors, Prokr1-KO mice with AAV rescue, myotube differentiation assays\",\n      \"pmids\": [\"38232288\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether PKR1 acts cell-autonomously in muscle fibers or also through paracrine mechanisms not fully resolved\",\n        \"Upstream regulation of PKR1 expression in skeletal muscle not characterized\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying celecoxib as a selective Gs-biased PROKR1 agonist that competes with PK2 binding and phenocopies PKR1-mediated oxidative fiber formation provided pharmacological validation of the Gs–CREB–NR4A2 muscle axis.\",\n      \"evidence\": \"Molecular docking, competitive binding assay, PROKR1 signaling in overexpressing cells, murine and human myotube assays, in vivo dietary exposure model\",\n      \"pmids\": [\"39887895\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Off-target effects of celecoxib via COX-2 inhibition not fully excluded in muscle phenotype\",\n        \"Whether celecoxib binds the orthosteric or allosteric pocket on PKR1 not structurally confirmed\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Conditional deletion of PKR1 in Tcf21⁺ epicardial cells revealed a PKR1→miR-124⊣SNAI2 axis controlling epicardial EMT and demonstrated that epicardial-derived miR-124 paracrinally suppresses cardiomyocyte contractility, linking PKR1 to intercellular communication in heart development.\",\n      \"evidence\": \"Conditional epicardial Tcf21-PKR1 knockout mice, transcriptomics, 3′UTR reporter, miR-124 inhibition rescue, conditioned media paracrine assays\",\n      \"pmids\": [\"41460181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct transcriptional mechanism by which PKR1 suppresses miR-124 not identified\",\n        \"Whether this axis operates in adult cardiac repair or only in development not tested\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrating that the non-peptide PKR1 agonist IS39 protects cardiomyocytes from doxorubicin toxicity via ROS reduction and antifibrotic signaling, abolished by PKR1 knockdown, confirmed druggability of the receptor's cardioprotective arm.\",\n      \"evidence\": \"Primary cardiomyocyte assays with PKR1 knockdown/antagonism, in vivo murine doxorubicin cardiotoxicity model\",\n      \"pmids\": [\"41860378\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream signaling pathway (Akt, CREB, or other) mediating IS39 cardioprotection not mapped\",\n        \"Long-term safety and receptor selectivity of IS39 in vivo not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structure of PROKR1 in complex with its ligands or G proteins has not been reported, leaving the structural basis for biased signaling, ligand selectivity between PK2 and PK2β, and the mechanism of variant effects (e.g., I379V) unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No cryo-EM or crystal structure of PROKR1 available\",\n        \"Mechanism by which PKR1 couples to both Gq/11 and Gs in different tissues not structurally explained\",\n        \"Full interactome of PROKR1 beyond G proteins not systematically defined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 4, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [2, 6, 7]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TRPV1\",\n      \"PROK2\",\n      \"NR4A2\",\n      \"SNAI2\",\n      \"RCAN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}