Affinage

PROKR2

Prokineticin receptor 2 · UniProt Q8NFJ6

Length
384 aa
Mass
44.0 kDa
Annotated
2026-04-28
62 papers in source corpus 24 papers cited in narrative 24 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PROKR2 is a G protein-coupled receptor for prokineticin ligands (PROK1/PROK2) that transduces signals through multiple G-protein subtypes (Gαq, Gαs, Gαi/o) and β-arrestins to regulate neuronal migration, circadian output, nociception, and reproductive physiology. Gαq/IP3/Ca²⁺ signaling is the principal pathway driving PROK2-induced cell migration and is selectively disrupted by most disease-causing mutations, while individual mutations can produce biased signaling by losing coupling to specific Gα subtypes or β-arrestin recruitment without affecting others (PMID:24830383, PMID:30576231, PMID:36694982). Receptor internalization is GRK2- and clathrin-dependent but β-arrestin-independent, and trafficking-deficient mutants undergo ER–Golgi cycling with enhanced ERAD, while N-linked glycosylation at N27 and the accessory proteins MRAP2 and Snapin regulate plasma membrane delivery and receptor stability (PMID:24509228, PMID:35173048, PMID:34483834, PMID:26687946). Loss-of-function PROKR2 mutations cause Kallmann syndrome and idiopathic hypogonadotropic hypogonadism through impaired GnRH neuron migration and olfactory bulb neurogenesis, whereas a gain-of-function frameshift variant has been linked to central precocious puberty (PMID:16537498, PMID:28338294, PMID:18826963).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2006 High

    Establishing PROKR2 as essential for olfactory bulb morphogenesis and GnRH neuron migration answered what developmental processes require this receptor and linked it to Kallmann syndrome pathogenesis.

    Evidence Pkr2−/− knockout mice showing olfactory bulb hypoplasia, absent hypothalamic GnRH neurons, and reproductive atrophy

    PMID:16537498

    Open questions at the time
    • Downstream intracellular signaling pathways mediating the migration phenotype were not identified
    • Cell-autonomous versus non-autonomous roles of PROKR2 in GnRH neuron migration not distinguished
  2. 2007 High

    Demonstrating that Prokr2-null mice lose circadian behavioral and thermoregulatory rhythms while retaining SCN oscillator function established PROKR2 as a circadian output pathway receptor rather than a clock component.

    Evidence Prokr2−/− mice with locomotor activity recording in LD/DD and bioluminescence SCN slice imaging

    PMID:17202262

    Open questions at the time
    • Identity of neurons downstream of PROKR2 that relay circadian signals is unknown
    • Whether PROKR2 and PROKR1 have redundant circadian roles was not tested
  3. 2007 High

    Showing that Prokr2-null neurospheres fail to migrate toward PROK2 and that olfactory bulb interneuron progenitors accumulate in the RMS established a direct chemotactic role for PROKR2 in postnatal neuroblast migration.

    Evidence BrdU labeling, doublecortin immunohistochemistry, and in vitro neurosphere migration assays in Prokr2-null mice

    PMID:18052978

    Open questions at the time
    • Signaling pathway coupling PROKR2 to cytoskeletal rearrangement during migration was not identified
  4. 2008 High

    Systematic functional analysis of ten KS-associated missense mutations revealed three distinct loss-of-function mechanisms—defective trafficking, abolished ligand binding, and impaired G-protein coupling—establishing the molecular basis of PROKR2 dysfunction in disease.

    Evidence Site-directed mutagenesis in HEK-293 cells with calcium release and surface expression assays for 10 mutations

    PMID:18826963

    Open questions at the time
    • G-protein coupling defects were inferred from loss of Ca²⁺ signaling; direct G-protein interaction was not measured
    • In vivo consequences of individual mutations not tested
  5. 2011 High

    Mapping the R164Q mutation to IL2 and showing it disrupts direct interaction with Gαq, Gαi, and Gα16 without affecting surface expression or ligand binding provided the first biochemical evidence for how a specific intracellular loop mediates G-protein coupling.

    Evidence Co-IP and GST pull-down of IL2 peptide with Gα subunits, mutagenesis, calcium signaling assays

    PMID:21454486

    Open questions at the time
    • Structural basis of the IL2–Gα interface not resolved at atomic level
    • Whether IL2 mutations affect Gαs coupling was not assessed
  6. 2013 High

    Defining that basic residues in the distal IL3 have separable roles in trafficking (RRK 270-272) versus G-protein coupling (RKR 264-266) refined the structure-function map of PROKR2 intracellular domains.

    Evidence Systematic deletion and charged substitution mutagenesis in IL3 with surface expression and calcium signaling assays

    PMID:23969157

    Open questions at the time
    • Which specific Gα subtype interacts with the IL3 RKR motif was not determined
  7. 2013 High

    Demonstrating that individual PROKR2 variants selectively impair Gαq (IP/Ca²⁺) versus Gαs (cAMP) pathways established the concept of pathway-selective (biased) signaling for disease-associated alleles.

    Evidence Parallel IP/Ca²⁺ and cAMP assays for multiple PROKR2 variants in HEK cells

    PMID:24276467

    Open questions at the time
    • Clinical phenotype correlation with specific signaling bias not established
  8. 2014 High

    Comprehensive profiling across Gq, Gs, Gi/o, β-arrestin, and ERK pathways showed that each KS mutation produces a unique signaling fingerprint, establishing PROKR2 as a model for multi-pathway biased signaling at a single GPCR.

    Evidence Calcium, cAMP, BRET/IP Gi/o, β-arrestin recruitment, and ERK assays for multiple mutants in HEK-293 cells

    PMID:24830383

    Open questions at the time
    • Physiological consequences of loss of β-arrestin recruitment (R80C) versus loss of Gq (R164Q) not compared in vivo
  9. 2014 High

    Dissecting internalization requirements showed that PK2-induced PKR2 endocytosis is GRK2- and clathrin-dependent but β-arrestin-independent, and that ERK1/2 activation occurs independently of internalization via Gβγ/PLC-β/MEK, separating trafficking from downstream signaling.

    Evidence Dominant-negative and siRNA knockdown of GRK2, β-arrestins, clathrin; PKC and MEK inhibitors; ERK phosphorylation assays

    PMID:24509228

    Open questions at the time
    • Identity of the GRK2-phosphorylated residues on PROKR2 is unknown
    • Whether alternative GRKs compensate for GRK2 loss was not tested
  10. 2014 High

    Pharmacological rescue of trafficking-deficient mutants by antagonist A457 (P290S) and chemical chaperone glycerol (P290S, W178S) demonstrated that misfolded PROKR2 can be chaperoned to the plasma membrane, opening therapeutic possibilities.

    Evidence Treatment of HEK cells expressing P290S, W178S, G234D with A457 or glycerol followed by surface expression and calcium signaling assays

    PMID:24753254

    Open questions at the time
    • In vivo rescue of reproductive phenotype not demonstrated
    • Mechanism by which A457 selectively rescues P290S but not W178S is unclear
  11. 2015 High

    Identification of Snapin as a C-terminal binding partner that reduces ligand-induced degradation of PKR2 without affecting signaling established a novel accessory protein role in PROKR2 post-endocytic trafficking.

    Evidence Yeast two-hybrid, GST pull-down, co-immunoprecipitation with domain mapping of PKR2 C-terminus (aa 333–384) and Snapin α-helices

    PMID:26687946

    Open questions at the time
    • Mechanism by which Snapin prevents degradation (lysosomal versus proteasomal) not defined
    • In vivo significance of Snapin–PKR2 interaction not tested
  12. 2017 High

    A truncated PROKR2 frameshift mutant that alone is inactive but paradoxically amplifies wild-type Ca²⁺ signaling in co-expression revealed a gain-of-function mechanism, linking PROKR2 to central precocious puberty.

    Evidence Patient mutation identification, in vitro expression with mutant-alone and WT co-transfection calcium assays

    PMID:28338294

    Open questions at the time
    • Molecular mechanism of the gain-of-function (allosteric modulation versus altered trafficking) is unknown
    • Replication in additional CPP families not reported
  13. 2018 High

    Demonstrating that R270H disrupts IL3 interaction with Gαq but not Gαs by direct pull-down provided biochemical proof that biased signaling arises from selective loss of a single Gα-protein interaction at a defined intracellular loop.

    Evidence GST pull-down of IL3 with Gαq and Gαs, plus IP/Ca²⁺, cAMP, and ERK assays for L218P and R270H

    PMID:30576231

    Open questions at the time
    • Structural determinants distinguishing Gαq versus Gαs docking sites on IL3 not resolved
  14. 2019 High

    Showing that Prokr2-null mice have reduced nociceptive sensitization to heat, capsaicin, protons, and cold implicated PROKR2 in pain pathways and revealed functional interactions with TRPV1 and TRPA1 channels.

    Evidence pkr2−/− mice with behavioral nociception assays and DRG culture co-stimulation experiments

    PMID:31883821

    Open questions at the time
    • Whether PROKR2 and TRPV1 physically interact was not tested in this study
    • Downstream signaling connecting PROKR2 to TRP channel sensitization not defined
  15. 2021 High

    Demonstrating that N-glycosylation at N27 is required for plasma membrane targeting and that MRAP2 prevents PKR2 surface delivery identified two distinct regulatory mechanisms controlling receptor bioavailability.

    Evidence Glycosylation site mutagenesis and MRAP2 co-expression with surface expression, cAMP, and calcium assays

    PMID:34483834

    Open questions at the time
    • Tissue-specific relevance of MRAP2-mediated inhibition of PROKR2 not established
    • Whether MRAP2 acts by retaining PROKR2 in the ER or promoting degradation is unclear
  16. 2022 High

    Interactome proteomics of the P290S trafficking mutant revealed that misfolded PROKR2 cycles between ER and Golgi and undergoes enhanced ERAD, with this cycling alleviating ER stress—providing a quality-control model for GPCR proteostasis.

    Evidence Interactome proteomics comparing WT versus P290S PROKR2, ERAD assays, ER–Golgi trafficking, ER stress measurements

    PMID:35173048

    Open questions at the time
    • Specific ERAD E3 ubiquitin ligase(s) targeting PROKR2 not identified
    • Whether pharmacological rescue interferes with the ERAD pathway was not tested
  17. 2023 High

    Establishing that Gαq signaling—not MAPK/ERK—is required for PROK2-induced cell migration and that most IHH mutations cluster in the Gαq-defective category unified the genotype-phenotype relationship for PROKR2-associated hypogonadotropic hypogonadism.

    Evidence Gαq pathway inhibitors blocking PROKR2-expressing cell migration; systematic functional classification of 63 IHH mutations

    PMID:36694982

    Open questions at the time
    • Whether Gαq-dependent migration requires PLCβ, PKC, or calcium downstream has not been dissected
    • Animal model validation of the pathogenicity classification is lacking
  18. 2025 Medium

    Demonstrating that TRPV1 physically interacts with PKR2 and modulates its activation, localization, and β-arrestin-2 recruitment established TRPV1 as a physiological regulator of PKR2 in nociceptive signaling.

    Evidence Co-immunoprecipitation, domain mapping, β-arrestin-2 recruitment assays, behavioral allodynia in vivo

    PMID:40139621

    Open questions at the time
    • Single-lab Co-IP; reciprocal validation and endogenous interaction confirmation needed
    • Stoichiometry and structural basis of the TRPV1–PKR2 complex are unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of PROKR2's selective coupling to Gαq versus Gαs versus Gαi/o at the atomic level, the in vivo therapeutic efficacy of pharmacological chaperone rescue of trafficking-deficient mutants, and the physiological role of MRAP2-mediated PROKR2 inhibition in specific tissues remain unresolved.
  • No high-resolution cryo-EM or crystal structure of PROKR2 in complex with any Gα subtype
  • In vivo pharmacological rescue of any PROKR2 trafficking mutant has not been demonstrated
  • Tissue-specific conditional knockout studies to separate PROKR2 roles in GnRH migration, circadian output, and nociception are lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1266738 Developmental Biology 3 R-HSA-112316 Neuronal System 2 R-HSA-9709957 Sensory Perception 2
Partners
GNAI1GNAQGNASGRK2MRAP2PROK1PROK2SNAPIN

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 PKR2 (PROKR2) is essential for normal olfactory bulb development and GnRH neuron migration to the hypothalamus; Pkr2-/- mice show olfactory bulb hypoplasia, absence of GnRH neurons in the hypothalamus, and severe reproductive system atrophy with reduced gonadotropin levels, establishing PROKR2 as required for these developmental processes. Targeted gene knockout mice (Pkr2-/-), immunohistochemistry, hormone assays, mRNA expression analysis Proceedings of the National Academy of Sciences of the United States of America High 16537498
2007 PROKR2 is required for circadian coordination of behavioral activity rhythms and thermoregulation by the suprachiasmatic nucleus (SCN), but is not necessary for intrinsic SCN oscillator function or light entrainment; Prokr2 null mice show disrupted onset/maintenance of nocturnal activity and depressed nocturnal body temperature. Targeted null mutation (Prokr2-/-), locomotor activity monitoring in LD and DD, bioluminescence real-time imaging of SCN slices, body temperature recording Proceedings of the National Academy of Sciences of the United States of America High 17202262
2007 PROKR2 is required for neuronal progenitor migration from the subventricular zone through the rostral migratory stream to the olfactory bulb; Prokr2 null mice show reduced BrdU+ cells, disrupted OB architecture, TUNEL+ nuclei in the glomerular layer, accumulation of doublecortin+ neuroblasts in the RMS, and Prokr2-deficient neurospheres fail to migrate toward PROK2 in vitro. Prokr2 null mice, BrdU labeling, TUNEL, immunohistochemistry (doublecortin, PSA-NCAM, tyrosine hydroxylase), in vitro neurosphere migration assay toward recombinant PROK2 The European journal of neuroscience High 18052978
2008 Ten KS-associated PROKR2 missense mutations impair receptor signaling through distinct mechanisms: three mutations (L173R, W178S, P290S) impair cell surface trafficking; one (Q210R) abolishes ligand binding; five (R85C, R85H, R164Q, R268C, V331M) presumably impair G protein coupling; none exert dominant-negative effects on co-expressed wild-type receptor. Site-directed mutagenesis of recombinant murine Prokr2, transfection in HEK-293 cells, intracellular calcium release assay, cell surface expression assays, co-expression experiments Human molecular genetics High 18826963
2011 The R164Q disease-causing mutation in the second intracellular loop (IL2) of PKR2 disrupts interaction of the IL2 loop with Gαq, Gαi, and Gα16 proteins without affecting cell surface expression or ligand binding; positive charge at position 164 is required for G-protein coupling, and the interactive partner of Arg-164 maps to the C-terminal five residues of Gαq; R164Q also reduces ligand-induced endocytosis. Site-directed mutagenesis, Co-IP/GST pull-down of IL2 loop with Gα subunits, calcium signaling assays, cell surface expression assays, endocytosis assays in transfected cells The Journal of biological chemistry High 21454486
2014 Wild-type PROKR2 can activate multiple G-protein subtypes (Gq, Gs, Gi/o) and recruit β-arrestins; KS-associated mutations cause biased signaling: R85C, R85H, R164Q, V331M show defective Gq signaling but retain β-arrestin recruitment; R80C activates all three G-protein types but cannot recruit β-arrestins; R268C activates Gq and Gs and recruits β-arrestins but cannot activate Gi/o. Transfection of HEK-293 cells with mutant PROKR2, calcium mobilization (Gq), cAMP (Gs), BRET/IP assays (Gi/o), β-arrestin recruitment assays FASEB journal : official publication of the Federation of American Societies for Experimental Biology High 24830383
2014 PK2-induced PKR2 endocytosis is GRK2-dependent and clathrin-dependent, but β-arrestin-independent; PKC activation also induces PKR2 endocytosis but is not required for PK2-induced endocytosis; PK2-induced ERK1/2 activation occurs independently of internalization and PKC, and likely involves released βγ subunits of G-protein, phospholipase C-β, and MEK. Dominant-negative and siRNA knockdown of GRK2, β-arrestins, clathrin; PKC inhibitor/activator experiments; ERK1/2 phosphorylation assays in transfected cells Cellular signalling High 24509228
2014 The PKR2 antagonist A457 rescues cell surface expression and signaling of the P290S trafficking-deficient mutant but not W178S or G234D mutants; chemical chaperone glycerol rescues cell surface expression and signaling of both P290S and W178S mutants, demonstrating differential pharmacological rescue mechanisms. Small molecule treatment (A457 antagonist, glycerol) of HEK cells expressing trafficking-deficient PKR2 mutants, cell surface expression assays, calcium signaling assays The Journal of biological chemistry High 24753254
2013 PROKR2 missense variants differentially affect Gαq (inositol phosphate/Ca2+) and Gαs (cAMP) signaling pathways: T260M, R268C, V331M show selective impairment of IP/Ca2+ with preserved cAMP; L173R and V274D abolish cAMP stimulation; V334M increases EC50 for both pathways; demonstrating pathway-selective effects of single allelic variants. Transfection of HEK cells with PROKR2 variants, inositol phosphate/Ca2+ assay (Gq), cAMP accumulation assay (Gs), cell surface expression measurement The Journal of clinical endocrinology and metabolism High 24276467
2013 Basic amino acids in the distal region of the third intracellular loop (IL3) of PROKR2 differentially regulate receptor trafficking and G-protein coupling: deletion of RRK (270-272) abolishes cell surface expression; deletion of RKR (264-266) preserves surface expression but abrogates G-protein coupling; charged substitution at V274 causes low surface expression and loss-of-function. Site-directed mutagenesis, deletion analysis, cell surface expression assays, calcium signaling assays in transfected cells Biochemical and biophysical research communications High 23969157
2015 Snapin is a novel interaction partner of PKR2, binding to the C-terminus (amino acids 333-384) via its two α-helix domains, with interaction motifs on PKR2 mapped to YFK (343-345) and HWR (351-353); Snapin interaction does not affect PKR2 signaling but reduces ligand-induced degradation, implying a role in PKR2 trafficking. Yeast two-hybrid screening, GST pull-down, co-immunoprecipitation, deletion/mutation mapping Biochemical and biophysical research communications High 26687946
2017 A heterozygous frameshift PROKR2 mutation generating a truncated receptor lacking two transmembrane domains and the C-terminal tail has no intrinsic signaling activity, but cells co-expressing mutant and wild-type PROKR2 show markedly exaggerated ligand-induced Ca2+ responses, demonstrating a paradoxical gain-of-function mechanism causing central precocious puberty. Patient mutation identification, in vitro expression of mutant PROKR2, calcium signaling assays with mutant-alone and mutant+wild-type co-transfections, NMD escape analysis Journal of cellular and molecular medicine High 28338294
2018 Two IHH-associated PROKR2 mutations (L218P and R270H) disrupt Gαq-dependent signaling while maintaining normal Gαs and ERK1/2 signaling; GST pull-down demonstrated that R270H disrupts the interaction of intracellular loop 3 of PROKR2 with Gαq but not Gαs, establishing selective Gα-protein interaction disruption as a mechanism of biased signaling. Functional assays (IP/Ca2+, cAMP, ERK1/2) in transfected cells, GST pull-down of PROKR2 intracellular loop 3 with Gαq and Gαs proteins FASEB journal : official publication of the Federation of American Societies for Experimental Biology High 30576231
2018 Co-transfection of wild-type and mutant PROKR2 in vitro better distinguishes pathogenic IGD variants from control variants than mutant-alone assays; 15/34 IGD variants cause loss-of-function under co-transfection conditions including 3 novel dominant-negatives; variants with LoF in ≥2 signaling assays under co-transfection are more likely disease-associated. In vitro functional assays (IP/Ca2+, cAMP, ERK1/2) with mutant-alone and mutant+WT co-transfection in HEK cells, across 59 PROKR2 variants Human molecular genetics High 29161432
2019 PROKR2 is expressed in postmitotic immature interneurons in the SVZ-RMS-OB pathway; PROK2/PROKR2 signaling is required for tangential and radial migration of olfactory bulb interneurons, with loss of ~75% of GABAergic interneurons in Prok2 and Prokr2 mutant mice. Prokr2LacZ/+ knockin and Prok2EGFP transgenic mice, immunohistochemistry for cell-type markers, BrdU labeling, quantification of GABAergic interneurons in OB The Journal of comparative neurology High 31132148
2019 PKR2 knockout mice show reduced nociceptive sensitization to heat (46-48°C), capsaicin, and protons, implicating a functional interaction between PKR2 and TRPV1; PKR2 KO mice also show reduced cold nociception and mustard oil-induced inflammatory hyperalgesia, suggesting functional interaction with TRPA1. pkr2 null mice, nociceptive behavioral assays (temperature, capsaicin, proton, cold, mustard oil), DRG cultures from PKR1-/- and PKR2-/- mice with Bv8 and mustard oil co-stimulation Neuroscience High 31883821
2021 N-linked glycosylation of PKR2 at position N27 in the N-terminal region is important for plasma membrane localization and signaling; glycosylation at N7 selectively decreases PKR2 signaling through Gαs without impairing Gαq/11 signaling; PKR2 is inhibited by the endogenous accessory protein MRAP2, which prevents it from trafficking to the plasma membrane. Site-directed mutagenesis of glycosylation sites, cell surface expression assays, Gαs (cAMP) and Gαq/11 (calcium) signaling assays, co-expression with MRAP2 Frontiers in neuroscience High 34483834
2022 Trafficking-deficient mutant PROKR2 (P290S) cycles between ER and Golgi rather than reaching the plasma membrane; both WT and P290S mutant are targeted for ER-associated degradation (ERAD), but the mutant is degraded to a greater extent; the post-ER cycling of the mutant to the Golgi and back reduces ER stress induced by the mutant. Interactome proteomics (WT vs P290S PROKR2), ERAD assays, ER-Golgi trafficking assays, ER stress measurements, subcellular fractionation Proceedings of the National Academy of Sciences of the United States of America High 35173048
2023 Gαq signaling (but not MAPK/ERK pathway) is required for PROK2-induced migration of PROKR2-expressing cells; 63 IHH-associated PROKR2 mutations were categorized by Gαq pathway functionality into four pathogenicity groups, establishing Gαq signaling disruption as the primary mechanism underlying PROKR2-related IHH. Systematic functional assays (Gαq, Gαs, ERK1/2) for 23 PROKR2 mutations in transfected cells, Gαq pathway inhibitor experiments with PROKR2-expressing cell migration assay Human molecular genetics High 36694982
2008 Cardiomyocyte-specific overexpression of PKR2 in transgenic mice causes eccentric cardiac hypertrophy (increased hypertrophic gene expression, increased cardiomyocyte length, increased ventricular diameters) and impaired endothelial integrity with vascular leakage through altered ZO-1 distribution, acting via autocrine (hypertrophy) and paracrine (endothelial) mechanisms. Transgenic mouse overexpressing PKR2 in cardiomyocytes, heart/body weight ratios, echocardiography, morphological analysis, ZO-1 immunostaining, conditioned media experiments on H5V endothelial cells Cardiovascular research High 18806277
2010 C. trachomatis infection increases PROKR2 mRNA in fallopian tube epithelium via TLR2 ligation and NFκB activation; dominant-negative TLR2 or IκBα transfection abrogates C. trachomatis-induced PROKR2 upregulation, establishing TLR2→NFκB→PROKR2 as an upstream regulatory pathway for PROKR2 expression. C. trachomatis infection of fallopian tube explants and OE-E6/E7 cells, dominant-negative TLR2 and IκBα transfection, qRT-PCR, immunohistochemistry The American journal of pathology High 21224062
2021 EG-VEGF (PROK1) activates ERK1/2 signaling and upregulates MMP-2 and MMP-9 in human trophoblast cells via PROKR2; anti-PROKR2 antibody suppresses EG-VEGF-induced ERK1/2 activation and inhibits trophoblast migration and invasion. Anti-PROKR2 antibody blockade in HTR-8/SVneo cells, western blotting for ERK1/2, MMP-2, MMP-9, Akt; wound-healing and invasion assays Acta medica Okayama Medium 34955534
2025 TRPV1 physically interacts with PKR2 and acts as a physiological regulator of PKR2, modulating its activation, localization, and β-arrestin-2 recruitment; the accessory protein snapin increases the binding strength between TRPV1 and PKR2; TRPV1 modulates PK2-induced mechanical allodynia. Co-immunoprecipitation, domain mapping of TRPV1-PKR2 interaction, β-arrestin-2 recruitment assays, localization studies, behavioral allodynia assay Cellular signalling Medium 40139621
2013 PROKR2 V331M variant decreases intracellular calcium influx but increases cell invasiveness of trophoblast cells, conferring lower risk for recurrent miscarriage, suggesting that altered calcium signaling via PROKR2 regulates trophoblast invasive behavior. Ectopic expression of PROKR2 V331M in HEK293 and JAR cells, intracellular calcium assay, cell invasion assay, cell proliferation and adhesion assays Reproduction (Cambridge, England) Medium 23687280

Source papers

Stage 0 corpus · 62 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2. Proceedings of the National Academy of Sciences of the United States of America 224 16537498
2007 Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei. Proceedings of the National Academy of Sciences of the United States of America 122 17202262
2008 The complex genetics of Kallmann syndrome: KAL1, FGFR1, FGF8, PROKR2, PROK2, et al. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 118 18987492
2008 PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity. Human molecular genetics 100 18826963
2012 PROKR2 variants in multiple hypopituitarism with pituitary stalk interruption. The Journal of clinical endocrinology and metabolism 64 22466334
2007 Olfactory bulb hypoplasia in Prokr2 null mice stems from defective neuronal progenitor migration and differentiation. The European journal of neuroscience 59 18052978
2010 Chlamydia trachomatis infection increases fallopian tube PROKR2 via TLR2 and NFκB activation resulting in a microenvironment predisposed to ectopic pregnancy. The American journal of pathology 53 21224062
2013 PROK2/PROKR2 Signaling and Kallmann Syndrome. Frontiers in endocrinology 51 23596439
2010 Kallmann syndrome caused by mutations in the PROK2 and PROKR2 genes: pathophysiology and genotype-phenotype correlations. Frontiers of hormone research 47 20389090
2013 Variations in PROKR2, but not PROK2, are associated with hypopituitarism and septo-optic dysplasia. The Journal of clinical endocrinology and metabolism 42 23386640
2007 Placental expression of EG-VEGF and its receptors PKR1 (prokineticin receptor-1) and PKR2 throughout mouse gestation. Placenta 42 17531315
2009 Possible association of prokineticin 2 receptor gene (PROKR2) with mood disorders in the Japanese population. Neuromolecular medicine 40 19544013
2014 Biased signaling through G-protein-coupled PROKR2 receptors harboring missense mutations. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 39 24830383
2017 Digenic Inheritance of PROKR2 and WDR11 Mutations in Pituitary Stalk Interruption Syndrome. The Journal of clinical endocrinology and metabolism 38 28453858
2015 FGFR1 and PROKR2 rare variants found in patients with combined pituitary hormone deficiencies. Endocrine connections 35 25759380
2008 Transgenic myocardial overexpression of prokineticin receptor-2 (GPR73b) induces hypertrophy and capillary vessel leakage. Cardiovascular research 35 18806277
2012 An ancient founder mutation in PROKR2 impairs human reproduction. Human molecular genetics 29 22773735
2013 Germline prokineticin receptor 2 (PROKR2) variants associated with central hypogonadism cause differental modulation of distinct intracellular pathways. The Journal of clinical endocrinology and metabolism 28 24276467
2019 The PROK2/PROKR2 signaling pathway is required for the migration of most olfactory bulb interneurons. The Journal of comparative neurology 27 31132148
2018 PROKR2 mutations in idiopathic hypogonadotropic hypogonadism: selective disruption of the binding to a Gα-protein leads to biased signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 25 30576231
2017 Paradoxical gain-of-function mutant of the G-protein-coupled receptor PROKR2 promotes early puberty. Journal of cellular and molecular medicine 24 28338294
2011 Expression of PROKR1 and PROKR2 in human enteric neural precursor cells and identification of sequence variants suggest a role in HSCR. PloS one 23 21858136
2018 Modeling mutant/wild-type interactions to ascertain pathogenicity of PROKR2 missense variants in patients with isolated GnRH deficiency. Human molecular genetics 21 29161432
2013 Greater prevalence of PROKR2 mutations in Kallmann syndrome patients from the Maghreb than in European patients. European journal of endocrinology 21 24031091
2012 PROKR2 and PROK2 mutations cause isolated congenital anosmia without gonadotropic deficiency. European journal of endocrinology 20 23082007
2017 Sexually dimorphic distribution of Prokr2 neurons revealed by the Prokr2-Cre mouse model. Brain structure & function 19 28616754
2014 Mechanisms that underlie the internalization and extracellular signal regulated kinase 1/2 activation by PKR2 receptor. Cellular signalling 19 24509228
2012 PROKR2 mutations in autosomal recessive Kallmann syndrome. Fertility and sterility 19 23200691
2011 Disease-causing mutation in PKR2 receptor reveals a critical role of positive charges in the second intracellular loop for G-protein coupling and receptor trafficking. The Journal of biological chemistry 19 21454486
2024 Targeting JAK2/STAT3, NLRP3/Caspase-1, and PK2/PKR2 Pathways with Arbutin Ameliorates Lead Acetate-Induced Testicular Injury in Rats. Pharmaceuticals (Basel, Switzerland) 16 39065759
2019 Abnormal Pain Sensation in Mice Lacking the Prokineticin Receptor PKR2: Interaction of PKR2 with Transient Receptor Potential TRPV1 and TRPA1. Neuroscience 16 31883821
2014 Functional rescue of Kallmann syndrome-associated prokineticin receptor 2 (PKR2) mutants deficient in trafficking. The Journal of biological chemistry 16 24753254
2010 PROKR2 is associated with methamphetamine dependence in the Japanese population. Progress in neuro-psychopharmacology & biological psychiatry 15 20576534
2013 Prokineticin receptor variants (PKR1-I379V and PKR2-V331M) are protective genotypes in human early pregnancy. Reproduction (Cambridge, England) 14 23687280
2015 Combined pituitary hormone deficiency with unique pituitary dysplasia and morning glory syndrome related to a heterozygous PROKR2 mutation. Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 12 25678757
2021 Role of N-Linked Glycosylation in PKR2 Trafficking and Signaling. Frontiers in neuroscience 10 34483834
2021 Control of hippocampal prothrombin kringle-2 (pKr-2) expression reduces neurotoxic symptoms in five familial Alzheimer's disease mice. British journal of pharmacology 10 34524687
2013 Functional analysis of the distal region of the third intracellular loop of PROKR2. Biochemical and biophysical research communications 10 23969157
2018 Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) and its receptor PROKR2 are associated to human colorectal cancer progression and peritoneal carcinomatosis. Cancer biomarkers : section A of Disease markers 9 29226856
2013 Multiplex ligation dependent probe amplification analysis of KAL1, GNRH1, GNRHR, PROK2 and PROKR2 in male patients with idiopathic hypogonadotropic hypogonadism. Endokrynologia Polska 9 24002956
2021 Molecular screening of PROKR2 gene in girls with idiopathic central precocious puberty. Italian journal of pediatrics 8 33413516
2021 Oligogenic Inheritance Underlying Incomplete Penetrance of PROKR2 Mutations in Hypogonadotropic Hypogonadism. Frontiers in genetics 8 34539727
2017 A heterozygous microdeletion of 20p12.2-3 encompassing PROKR2 and BMP2 in a patient with congenital hypopituitarism and growth hormone deficiency. American journal of medical genetics. Part A 7 28586151
2017 Kallmann syndrome with a Tyr113His PROKR2 mutation. Medicine 7 28858133
2015 Snapin interacts with G-protein coupled receptor PKR2. Biochemical and biophysical research communications 7 26687946
2023 Phenotypic and genotypic landscape of PROKR2 in neuroendocrine disorders. Frontiers in endocrinology 6 36843573
2021 Comparison of Clinical Characteristics and Spermatogenesis in CHH Patients Caused by PROKR2 and FGFR1 Mutations. Reproductive sciences (Thousand Oaks, Calif.) 6 33983622
2009 Cloning and developmental expression analysis of prokineticin 2 and its receptor PKR2 in the Syrian hamster surpachiasmatic nucleus. Brain research 6 19327346
2021 Pressure Overload-Mediated Sustained PKR2 (Prokineticin-2 Receptor) Signaling in Cardiomyocytes Contributes to Cardiac Hypertrophy and Endotheliopathies. Hypertension (Dallas, Tex. : 1979) 5 33677981
2016 Association between polymorphisms of prokineticin receptor (PKR1 rs4627609 and PKR2 rs6053283) and recurrent pregnancy loss. Journal of Zhejiang University. Science. B 5 26984842
2023 A functional spectrum of PROKR2 mutations identified in isolated hypogonadotropic hypogonadism. Human molecular genetics 4 36694982
2023 pKr-2 induces neurodegeneration via upregulation of microglial TLR4 in the hippocampus of AD brain. Brain, behavior, & immunity - health 4 36798617
2023 PROKR2 Mutations in Patients with Short Stature Who Have Isolated Growth Hormone Deficiency and Multiple Pituitary Hormone Deficiency. Journal of clinical research in pediatric endocrinology 4 37338295
2022 Trafficking-defective mutant PROKR2 cycles between endoplasmic reticulum and Golgi to attenuate endoplasmic reticulum stress. Proceedings of the National Academy of Sciences of the United States of America 4 35173048
2024 Additional mutation in PROKR2 and phenotypic differences in a Kallmann syndrome/normosmic congenital hypogonadotropic hypogonadism family carrying FGFR1 missense mutation. BMJ case reports 3 38272512
2022 Biallelic PROKR2 variants and congenital hypogonadotropic hypogonadism: a case report and a literature review. Endocrine journal 3 35236788
2021 EG-VEGF Induces Invasion of a Human Trophoblast Cell Line via PROKR2. Acta medica Okayama 3 34955534
2017 PKR2 and β-catenin genes regulates pancreatic cancer chemosensitivity. European review for medical and pharmacological sciences 3 28121357
2025 Physical TRPV1-PKR2 interaction modulates PKR2 localization, activation and β-arrestin-2 recruitment. Cellular signalling 1 40139621
2022 [Analysis of PROKR2 gene mutation in patients with hypogonadotropic hypogonadism]. Zhonghua nei ke za zhi 1 35922219
2025 Expanding the phenotypic spectrum of PROK2/PROKR2: a recall-by-genotype study. Human genetics 0 40498399
2024 46 XX Ovotesticular Disorder of Sex Development with Gonadotropin-Releasing Hormone Receptor, Autosomal Recessive Heterozygous Missense Mutation and Autosomal Dominant Heterozygous Missense Mutation of the PROKR2 Gene: A Case Report. Global medical genetics 0 38988852