PROKR1

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).

1. 2006 High

   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

   PMID:16793879

   Open questions at the time

   • 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
2. 2007 High

   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

   PMID:17442730

   Open questions at the time

   • G protein coupling specificity for Akt activation in cardiomyocytes not determined
   • Direct targets downstream of Akt in this context not identified
3. 2009 High

   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

   PMID:19801577

   Open questions at the time

   • 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
4. 2011 Medium

   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

   PMID:21856786

   Open questions at the time

   • 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
5. 2013 Medium

   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

   PMID:23687280

   Open questions at the time

   • 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
6. 2018 Medium

   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

   PMID:30253862

   Open questions at the time

   • 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
7. 2024 High

   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

   PMID:38232288

   Open questions at the time

   • 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
8. 2025 Medium

   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

   PMID:39887895

   Open questions at the time

   • 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
9. 2026 High

   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

   PMID:41460181

   Open questions at the time

   • 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
10. 2026 Medium

    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

    PMID:41860378

    Open questions at the time

    • Downstream signaling pathway (Akt, CREB, or other) mediating IS39 cardioprotection not mapped
    • Long-term safety and receptor selectivity of IS39 in vivo not established

• 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.
• 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