Affinage

NPR2

Atrial natriuretic peptide receptor 2 · UniProt P20594

Length
1047 aa
Mass
117.0 kDa
Annotated
2026-04-29
100 papers in source corpus 32 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NPR2 (natriuretic peptide receptor B / guanylyl cyclase B) is a homodimeric transmembrane receptor guanylyl cyclase that binds C-type natriuretic peptide (CNP) through its extracellular domain and converts GTP to cGMP, functioning as a critical signaling hub in oocyte meiotic arrest, endochondral bone growth, and sensory axon bifurcation (PMID:15146390, PMID:20947764, PMID:17954614). Its catalytic activity is governed by phosphorylation of seven juxtamembrane serine/threonine residues in the kinase homology domain: full phosphorylation is required for enzymatic competence, while dephosphorylation by PPP-family phosphatases—triggered by LH signaling in ovarian follicles or FGF signaling in growth plate chondrocytes—rapidly inactivates the receptor without altering protein levels or surface expression (PMID:26522847, PMID:25183874, PMID:29199951, PMID:15459247). Elevated intracellular calcium, downstream of EGFR, vasopressin, or sphingosine-1-phosphate receptor activation, independently inactivates NPR2 guanylyl cyclase activity in a PKC-independent manner (PMID:12196532, PMID:23787120, PMID:16005434). Loss-of-function mutations in NPR2 cause acromesomelic dysplasia type Maroteaux (AMDM), primarily through ER retention of misfolded receptor or catalytic impairment, while gain-of-function mutations produce overgrowth, and in the nervous system NPR2 loss abolishes T-shaped bifurcation of sensory axons at spinal cord and hindbrain entry zones via a cGMP-dependent protein kinase Iα pathway (PMID:18945719, PMID:24259409, PMID:17954614, PMID:24431432).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2002 High

    The question of how Gq-coupled receptor signaling desensitizes NPR2 was resolved by showing that elevated intracellular calcium—not PKC—is the required second messenger for vasopressin-induced NPR-B inactivation, establishing calcium as a key regulator of this guanylyl cyclase.

    Evidence Pharmacological dissection (BAPTA-AM, ionomycin, PKC downregulation) with cGMP accumulation assays in A10 vascular smooth muscle cells

    PMID:12196532

    Open questions at the time
    • Identity of the calcium-sensitive phosphatase or direct effector acting on NPR2 was not determined
    • Whether calcium acts directly on NPR2 or through an intermediate was unknown
  2. 2004 High

    NPR2 was established as a homodimeric guanylyl cyclase whose loss-of-function mutations cause AMDM, directly linking enzymatic activity to human skeletal disease and confirming the receptor's essential role in bone elongation.

    Evidence Functional cGMP assays of AMDM patient-derived missense mutants, family segregation analysis, and molecular modeling

    PMID:15146390 PMID:15459247

    Open questions at the time
    • Mechanism by which individual mutations impair activity (misfolding vs. catalytic defect) was not yet distinguished
    • NPR2 desensitization was shown to occur without receptor internalization but the mechanism remained unclear
  3. 2005 High

    A spontaneous loss-of-function mutation in the guanylyl cyclase domain of Npr2 was shown to abolish CNP-stimulated cGMP in chondrocytes and cause dwarfism, providing genetic proof that NPR2 catalytic activity directly controls longitudinal bone growth.

    Evidence Linkage analysis and cGMP assays in primary chondrocytes and COS-7 cells from cn/cn mice

    PMID:15722353

    Open questions at the time
    • Downstream signaling pathway from cGMP to chondrocyte proliferation/hypertrophy was not defined
    • Whether the skeletal phenotype requires NPR2 activity specifically in cartilage was untested
  4. 2007 High

    The discovery that Npr2-null embryos lack T/Y-shaped bifurcation of sensory axons at the dorsal root entry zone—with cGKIα acting downstream—revealed a wholly unexpected developmental function for NPR2 in axon guidance independent of its endocrine roles.

    Evidence Genetic knockout and inactive Npr2 mice, axon tracing with DiI, patch-clamp electrophysiology, epistasis with cGKI mutants

    PMID:17954614

    Open questions at the time
    • The axonal substrate of cGKI that mediates bifurcation was unknown
    • Source of CNP ligand in the spinal cord was not identified
  5. 2008 High

    Systematic analysis of AMDM missense mutations revealed that the predominant pathogenic mechanism is ER retention of misfolded NPR2 rather than catalytic-site disruption, explaining why most mutations map throughout the extracellular and intracellular domains.

    Evidence Confocal microscopy with ER markers and cGMP assays for 12 missense mutants in HeLa cells

    PMID:18945719

    Open questions at the time
    • Whether ER-retained mutants exert dominant-negative effects on wild-type NPR2 was not tested
    • Contribution of ER stress to chondrocyte pathology was not examined
  6. 2010 High

    The NPPC/NPR2/cGMP axis was identified as the essential paracrine system maintaining oocyte meiotic arrest: mural granulosa cells produce CNP, cumulus cells express NPR2 to generate cGMP, and cGMP diffuses to oocytes via gap junctions to inhibit PDE3A.

    Evidence Reciprocal genetic knockouts (Nppc and Npr2 mutant mice) with cGMP assays and meiotic resumption scoring

    PMID:20947764

    Open questions at the time
    • How LH signaling reverses the NPR2-cGMP system was not yet defined
    • Whether NPR2 in mural granulosa cells also contributes was unclear
  7. 2012 High

    Multiple studies resolved the two-phase mechanism of LH-induced meiotic resumption: LH first rapidly inactivates NPR2 guanylyl cyclase activity (within 20 min, without reducing protein), then reduces CNP ligand availability—while simultaneously establishing that NPR2 suppresses MEK/ERK signaling in growth plate chondrocytes.

    Evidence Follicle membrane GC activity assays post-LH, Npr2 mutant mouse growth plate histology with ERK phosphorylation and MEK inhibitor rescue

    PMID:22546688 PMID:22696190 PMID:23065701

    Open questions at the time
    • The phosphatase responsible for NPR2 dephosphorylation was not identified
    • Whether NPR2 inhibits ERK through cGMP-dependent kinase or a parallel mechanism was untested
  8. 2013 High

    Heterozygous NPR2 mutations were shown to exert dominant-negative effects on wild-type NPR2 in co-transfection assays, explaining why heterozygous carriers have short stature—a dosage-sensitivity mechanism consistent with the homodimeric receptor architecture.

    Evidence Co-transfection of mutant and wild-type NPR2 with cGMP readout, patient sequencing

    PMID:24001744 PMID:24259409

    Open questions at the time
    • Structural basis of dominant-negative interaction within the homodimer was not resolved
    • Population frequency of heterozygous NPR2 variants contributing to idiopathic short stature was uncertain
  9. 2013 High

    EGFR signaling was placed upstream of NPR2 inactivation: EGF elevates intracellular calcium in cumulus cells, which decreases NPR2 guanylyl cyclase activity and reduces cGMP to trigger meiotic resumption, unifying the calcium-dependent desensitization mechanism with the ovarian physiology.

    Evidence Calcium imaging, cGMP ELISA, BAPTA-AM rescue, and AG1478 inhibition in cumulus-oocyte complexes

    PMID:23787120

    Open questions at the time
    • Whether calcium acts through a phosphatase to dephosphorylate NPR2 or through a distinct mechanism was not resolved
  10. 2014 High

    NPR2-dependent axon bifurcation was extended to cranial sensory ganglia (gV–gX) and shown to require cGKIα, while loss of Npr2 in spiral ganglion neurons disrupted tonotopic mapping in cochlear nuclei, establishing NPR2 as a pan-sensory bifurcation signal.

    Evidence Conditional Npr2 knockout with CreER(T2), axon tracing, auditory brainstem responses and in vivo electrophysiology

    PMID:24431432 PMID:25473838

    Open questions at the time
    • Mechanism by which cGMP/cGKI controls cytoskeletal dynamics at branch points was not identified
    • Whether bifurcation failure produces sensory behavioral deficits beyond auditory tonotopy was untested
  11. 2015 High

    Phosphorylation of NPR2's seven juxtamembrane serine/threonine residues was proven to be the switch controlling its activity in vivo: a phosphomimetic Npr2-7E knock-in mouse resisted LH-induced inactivation and showed delayed meiotic resumption, while cartilage-specific NPR2 knockout confirmed growth plate-autonomous function.

    Evidence Npr2-7E knock-in mouse with GC activity, cGMP, and meiosis assays; cartilage-specific conditional knockout with bone length measurements

    PMID:26014585 PMID:26522847

    Open questions at the time
    • The specific phosphatase(s) that dephosphorylate NPR2 in vivo remain unidentified
    • Whether phosphorylation status also regulates NPR2 in neurons was unknown
  12. 2017 High

    FGF signaling was shown to inactivate NPR2 in growth plate chondrocytes via PPP-family phosphatase-mediated dephosphorylation, providing the molecular mechanism by which FGFR3 gain-of-function (achondroplasia) antagonizes NPR2-dependent bone elongation.

    Evidence In vivo cGMP imaging in intact tibiae, non-dephosphorylatable NPR2 knock-in mouse resistant to FGF inhibition, PPP phosphatase inhibitor rescue

    PMID:29199951

    Open questions at the time
    • Identity of the specific PPP-family phosphatase acting on NPR2 was not determined
    • Whether FGF and LH use the same or distinct phosphatases is unresolved
  13. 2018 High

    Phosphorylation-dependent regulation was confirmed in neurons: a non-phosphorylatable Npr2-7A knock-in abolished CNP-induced cGMP and axon bifurcation, while phosphomimetic Npr2-7E sustained normal bifurcation, unifying the phospho-switch mechanism across skeletal, reproductive, and neural contexts.

    Evidence Dual knock-in mice (Npr2-7A, Npr2-7E), real-time cGMP imaging with fluorescent biosensor in DRG neurons, axon tracing

    PMID:30249793

    Open questions at the time
    • Whether dynamic dephosphorylation of NPR2 occurs during axon pathfinding is untested
    • Upstream signals controlling NPR2 phosphorylation state in neurons are unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity of the specific PPP-family phosphatase(s) responsible for NPR2 dephosphorylation in vivo, the structural basis of phosphorylation-dependent activation, and the cytoskeletal effectors downstream of cGKI that execute axon bifurcation remain unresolved.
  • No phosphatase has been specifically identified as the NPR2-inactivating enzyme in any tissue
  • No crystal structure of the phosphorylated vs. dephosphorylated kinase homology domain exists
  • The cytoskeletal substrate of cGKI mediating growth cone splitting at branch points is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0009975 cyclase activity 6 GO:0140299 molecular sensor activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-1474165 Reproduction 8 R-HSA-112316 Neuronal System 5 R-HSA-1266738 Developmental Biology 5
Partners
NPPCPDE5APRKG1

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 Mural granulosa cells express NPPC ligand while cumulus cells express NPR2 (a guanylyl cyclase receptor); NPPC binding to NPR2 increases cGMP in cumulus cells and oocytes, maintaining meiotic arrest. Npr2 or Nppc mutant mice show precocious meiotic resumption, establishing the NPPC/NPR2/cGMP axis as essential for meiotic arrest. Genetic knockout mice (Nppc and Npr2 mutants), in vitro cGMP assays, meiotic resumption assays Science High 20947764
2004 NPR2 functions as a homodimeric transmembrane guanylyl cyclase that produces cGMP in response to CNP binding to its extracellular domain; missense mutations causing AMDM show markedly deficient guanylyl cyclase activity in functional assays. Functional guanylyl cyclase activity assays of missense mutants, molecular modeling, sequencing of AMDM families American journal of human genetics High 15146390
2005 A loss-of-function missense mutation (Leu→Arg) in the guanylyl cyclase domain of Npr2 abolishes CNP-stimulated cGMP production in chondrocytes and COS-7 cells, causing disproportionate dwarfism in cn/cn mice, demonstrating that NPR2 guanylyl cyclase activity drives longitudinal bone growth. Linkage analysis, Sanger sequencing, intracellular cGMP assay in cultured chondrocytes and transfected COS-7 cells The Journal of biological chemistry High 15722353
2007 NPR2 (guanylyl cyclase B) is essential for T/Y-shaped bifurcation of sensory axons at the dorsal root entry zone; Npr2-inactive embryonic mice lack bifurcation (axons turn only rostrally or caudally), a defect associated with reduced synaptic input to superficial spinal cord layers. cGMP-dependent protein kinase I (cGKI) acts downstream in the same pathway. Genetic knockout/inactive Npr2 and cGKI mice, axon tracing, patch-clamp electrophysiology The Journal of cell biology High 17954614
2012 LH reduces NPR2 guanylyl cyclase activity in mouse ovarian follicles within 20 min (without reducing NPR2 protein levels), and at 2 h also reduces CNP availability; both mechanisms contribute to decreased cGMP that triggers meiotic resumption. Guanylyl cyclase activity assay in follicle membranes after LH treatment, Western blotting, in vitro follicle culture Developmental biology High 22546688
2014 LH signaling causes rapid dephosphorylation of NPR2 via PPP-family phosphatases within 10 min, inactivating its guanylyl cyclase activity and reducing cGMP to trigger meiotic resumption in rat oocytes; concurrently PDE5 is phosphorylated and activated. Phosphoprotein analysis, pharmacological inhibition of PPP phosphatases, cGMP assay, rat follicle culture Development High 25183874
2015 Phosphorylation of the seven juxtamembrane serine/threonine residues in the kinase homology domain of NPR2 is required for its guanylyl cyclase activity and for LH-induced meiotic resumption; a phosphomimetic Npr2-7E knock-in mouse fails to show LH-induced NPR2 inactivation and shows delayed meiotic resumption. Knock-in mouse (Npr2-7E), guanylyl cyclase activity assay, cGMP measurement, LH-stimulated meiosis assay Developmental biology High 26522847
2002 Vasopressin-dependent desensitization (inactivation) of NPR-B in vascular smooth muscle cells requires elevated intracellular calcium (not PKC); calcium chelator BAPTA-AM blocks AVP-dependent NPR-B desensitization, while calcium ionophore ionomycin mimics it. cGMP accumulation assays, PKC downregulation, BAPTA-AM chelation, ionomycin treatment in A10 cells The Journal of biological chemistry High 12196532
2004 NPR-A and NPR-B do not internalize or undergo down-regulation in response to natriuretic peptide binding; desensitization occurs without receptor internalization, as shown by cleavable and non-cleavable biotinylation assays. Cleavable/non-cleavable biotinylation assays, quantitative partition analysis, HPLC fractionation, 125I-ANP binding in 293T cells Molecular pharmacology High 15459247
2005 Sphingosine-1-phosphate (S1P) potently inhibits NPR-B guanylyl cyclase activity in fibroblasts and vascular smooth muscle cells via a cell-surface receptor in a calcium-dependent, PKC-independent mechanism, requiring elevated intracellular calcium. cGMP accumulation assay, membrane guanylyl cyclase activity assay, pharmacological inhibitors (BAPTA, PKC inhibitors) in NIH3T3 and A10 cells Biochemical pharmacology High 16005434
2004 S1P inhibits CNP-dependent NPR-B activation in vascular smooth muscle cells; the inhibition is rapid (t1/2=2-5 min), dose-dependent, mediated by a cell-surface receptor, and requires elevated intracellular calcium but not PKC. cGMP accumulation assay, membrane guanylyl cyclase activity assay, dose-response in A10 and NIH3T3 cells Hypertension Medium 15037564
2008 Missense mutations in NPR-B causing AMDM primarily act by trapping the receptor in the endoplasmic reticulum (ER), preventing trafficking to the plasma membrane; 11 of 12 missense mutants were ER-retained, while the only cell-surface-targeted mutant (D176E) had impaired ligand binding. Site-directed mutagenesis, confocal microscopy with ER marker co-localization, CNP-dependent cGMP assays in HeLa cells Human molecular genetics High 18945719
2011 Estradiol promotes and maintains NPR2 expression in cumulus cells, sustaining their ability to produce cGMP in response to NPPC and thereby maintaining oocyte meiotic arrest in vitro; loss of estradiol causes rapid loss of functional NPR2. In vitro culture of cumulus-oocyte complexes, qRT-PCR for Npr2 mRNA, cGMP assay, meiotic resumption scoring Endocrinology High 21914782
2012 CNP/NPR2 signaling maintains meiotic arrest in early antral follicles; Npr2 mutation causes precocious meiotic resumption at the early antral stage. NPPC/NPR2 is also required for cumulus oophorus formation, and its loss causes abnormal oocyte chromosomes and failure of oocyte developmental capacity. Analysis of Npr2(cn) and Nppc(lbab) mutant mice, histology, fertilization assays Reproduction High 22696190
2012 CNP/NPR2 signaling in early antral follicles maintains meiotic arrest; LH/amphiregulin/EGFR signaling suppresses NPPC mRNA in granulosa cells, thereby reducing ligand availability and relieving NPR2-dependent meiotic arrest. Npr2 mutant mouse histology, granulosa cell culture with amphiregulin treatment, qRT-PCR for Nppc and Npr2 Molecular reproduction and development High 22987720
2013 EGF receptor signaling elevates intracellular calcium in cumulus cells, which decreases NPR2 guanylyl cyclase activity (reducing cGMP), leading to meiotic resumption; calcium chelation blocks EGF-induced cGMP decrease and meiotic resumption. Cumulus-oocyte complex culture, calcium imaging, cGMP ELISA, EGF receptor inhibitor AG1478 and calcium chelator BAPTA-AM Endocrinology High 23787120
2014 Bifurcation of cranial sensory axons (ganglia gV, gVII, gVIII, gIX, gX) requires Npr2 and cGKIα activity; loss of Npr2 prohibits bifurcation of cranial sensory axons at their entry regions, while collateral formation is unaffected. Npr2-lacZ reporter mouse, Npr2-CreER(T2) conditional knockout, axon tracing, cell-type specific expression analysis The Journal of neuroscience High 24431432
2017 FGF signaling causes dephosphorylation of NPR2 (requiring a PPP-family phosphatase), reducing its guanylyl cyclase activity and cyclic GMP production in growth plate chondrocytes, thereby inhibiting bone elongation. A non-dephosphorylatable NPR2 knock-in mouse shows increased bone elongation and resistance to FGF-induced inhibition. In vivo cGMP imaging in intact tibia, knock-in mouse (non-dephosphorylatable NPR2), pharmacological FGF receptor activation, guanylyl cyclase activity assays eLife High 29199951
2018 Phosphorylation of the seven juxtamembrane serine/threonine residues in Npr2's kinase homology domain is required for CNP-induced cGMP generation and for axon bifurcation of DRG and cranial sensory neurons; a non-phosphorylatable Npr2-7A knock-in mouse lacks CNP-induced cGMP and shows bifurcation defects, while phosphomimetic Npr2-7E mice have normal bifurcation. Knock-in mice (Npr2-7A and Npr2-7E), real-time cGMP imaging in DRG neurons with fluorescent sensor, biochemical guanylyl cyclase assays, axon tracing The Journal of neuroscience High 30249793
2012 Loss of Npr2 causes a reduction in hypertrophic and proliferative zones of the growth plate, increased ERK1/2 activation in mutant tibiae, and the growth defect is rescued by MEK/ERK inhibitors (U0126, PD325901), placing NPR2 signaling upstream of MEK/ERK inhibition in chondrocytes. Npr2(pwe) loss-of-function mouse, growth plate histology, ERK phosphorylation Western blot, fetal tibia explant rescue with MEK inhibitors Human molecular genetics High 23065701
2015 Cartilage-specific knockout of GC-B (NPR2) causes severe bone shortening comparable to systemic knockout, demonstrating that the local CNP/NPR2 system within the growth plate is responsible for physiological endochondral bone growth. Cartilage-specific conditional knockout mice, bone length measurements, growth plate histology, proliferation assays Scientific reports High 26014585
2013 Heterozygous NPR2 missense mutations (Ser76Pro, Arg263Pro, Arg819Cys) identified in short-stature patients fail to produce cGMP after CNP stimulation, and co-transfection with wild-type NPR2 shows a dominant-negative effect, reducing cGMP output below wild-type levels. In vitro cell-based cGMP assay, co-transfection with mutant and wild-type NPR2, sequencing The Journal of clinical endocrinology and metabolism High 24001744
2014 NPR2 mutation R110C causes defective trafficking from the ER to the Golgi apparatus, while Q417E reaches the cell surface but is catalytically impaired; both have dominant-negative effects on cGMP production, demonstrating that distinct molecular pathogenesis underlies NPR2 loss-of-function. Subcellular localization by confocal microscopy, cGMP assay, co-transfection dominant-negative analysis in cultured cells The Journal of clinical endocrinology and metabolism High 24471569
2013 A gain-of-function NPR2 missense mutation (Ala488Pro) causes overactivity of the receptor at baseline and with ligand in vitro, leading to overgrowth syndrome, confirming that NPR2 guanylyl cyclase activity level directly controls longitudinal bone growth. In vitro transfection cGMP assay, family segregation analysis American journal of medical genetics. Part A Medium 24259409
2007 In congestive heart failure, NPR-A guanylyl cyclase activity is dramatically reduced without changes in NPR-B activity, making NPR-B (NPR2) the predominant natriuretic peptide-dependent guanylyl cyclase in the failing heart. Membrane guanylyl cyclase activity assays in normal vs. transaortic-banding CHF mouse heart preparations, echocardiography Endocrinology High 17412809
2010 CNP activates NPR2 (GC-B) in 3T3-L1 preadipocytes to elevate cGMP, which through cGMP-dependent kinase (cGK) signaling promotes adipogenesis; CNP can replace IBMX in the standard adipogenic cocktail, and a cGK inhibitor blocks IBMX-stimulated adipogenesis. cGMP assay, Oil Red O staining, adipogenic gene expression (PPARγ, GLUT4 mRNA), cGK inhibitor KT5823 Peptides Medium 20603173
2014 Npr2 mutation disrupts the tonotopic organization of spiral ganglion neuron projections within cochlear nuclei; central SGN processes fail to bifurcate, leading to underinnervation of the aVCN and blurred tonotopy, with intermittent failures in action potential conduction at branch points. Npr2 mutant mice, auditory brainstem responses, in vivo electrophysiology, anatomical tracing PLoS genetics High 25473838
2021 Elevated S1P in Sgpl1-knockout mice decreases NPR2 activity in granulosa cells, inhibiting early follicle growth and blocking oocyte development, establishing a mechanistic link between sphingolipid metabolism and NPR2 activity in vivo. Sgpl1 knockout mice, NPR2 activity assays, follicle histology, S1P measurement Cell death & disease Medium 34083520
2017 NPR2 localizes not only in bovine cumulus cell membranes but also directly in bovine oocyte membranes, and CNP directly activates intra-oocyte cGMP production via oocyte-localized NPR2, a mechanism distinct from the cumulus-cell-mediated pathway seen in mice. Immunofluorescence localization, cGMP assay in isolated oocytes, species comparison Theriogenology Medium 29080478
2022 Several NPR2 missense variants cause ER stress and accumulation of misfolded protein in the ER, leading to decreased chondrocyte differentiation (reduced ColII, ColX, BMP4; elevated Sox9) and increased apoptosis via the unfolded protein response (elevated GRP78, p-IRE1α). Overexpression in HEK293T and ATDC5 cells, ER stress markers (GRP78, p-IRE1α), differentiation markers, apoptosis assays, N-glycosylation analysis Cells Medium 35455946
2018 Loss of Npr2 in mesencephalic trigeminal neurons (MTNs) prevents their axon bifurcation in rhombomere 2 and reduces maximal bite force in conditional Npr2;Engr1 mutant mice, demonstrating that Npr2-dependent bifurcation of MTN afferents is required for normal sensory feedback from jaw muscles. Conditional Npr2;Engr1 knock-out mice, axon tracing in MTNs, bite force measurement Frontiers in cellular neuroscience High 29962937
2008 The CNP(lbab) mutation (Arg→Gly) in the CNP ligand reduces its binding affinity to NPR-B by ~10-fold, requiring 30-100-fold more CNP(lbab) to activate NPR-B cGMP production, explaining dwarfism in lbab mice through impaired ligand-receptor interaction. Whole cell cGMP elevation assay, membrane guanylyl cyclase assay, competitive radioligand binding, molecular modeling Peptides High 18554750
2014 NPR2 expression in the follicle is predominantly in mural granulosa cells; dephosphorylation of NPR2 in mural granulosa cells (not only cumulus cells) is essential for LH-induced meiotic resumption, as shown by the phosphomimetic Npr2-7E knock-in. Knock-in mouse (Npr2-7E), immunofluorescence localization of NPR2 protein, guanylyl cyclase activity after LH, cGMP measurement Developmental biology High 26522847

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Granulosa cell ligand NPPC and its receptor NPR2 maintain meiotic arrest in mouse oocytes. Science (New York, N.Y.) 454 20947764
2004 Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. American journal of human genetics 264 15146390
2005 Heterozygous mutations in natriuretic peptide receptor-B (NPR2) are associated with short stature. The Journal of clinical endocrinology and metabolism 132 16384845
2011 Estradiol promotes and maintains cumulus cell expression of natriuretic peptide receptor 2 (NPR2) and meiotic arrest in mouse oocytes in vitro. Endocrinology 130 21914782
2009 A genome-wide screen for regulators of TORC1 in response to amino acid starvation reveals a conserved Npr2/3 complex. PLoS genetics 126 19521502
2012 Luteinizing hormone reduces the activity of the NPR2 guanylyl cyclase in mouse ovarian follicles, contributing to the cyclic GMP decrease that promotes resumption of meiosis in oocytes. Developmental biology 112 22546688
2005 A loss-of-function mutation in natriuretic peptide receptor 2 (Npr2) gene is responsible for disproportionate dwarfism in cn/cn mouse. The Journal of biological chemistry 110 15722353
2013 Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature in patients initially classified as idiopathic short stature. The Journal of clinical endocrinology and metabolism 108 24001744
2007 Differential regulation of membrane guanylyl cyclases in congestive heart failure: natriuretic peptide receptor (NPR)-B, Not NPR-A, is the predominant natriuretic peptide receptor in the failing heart. Endocrinology 97 17412809
2014 Dephosphorylation and inactivation of NPR2 guanylyl cyclase in granulosa cells contributes to the LH-induced decrease in cGMP that causes resumption of meiosis in rat oocytes. Development (Cambridge, England) 88 25183874
2015 Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature. Human mutation 79 25703509
2011 Selective regulation of autophagy by the Iml1-Npr2-Npr3 complex in the absence of nitrogen starvation. Molecular biology of the cell 78 21900499
2005 Human CD57+ germinal center-T cells are the major helpers for GC-B cells and induce class switch recombination. BMC immunology 76 15694005
2012 CNP/NPR2 signaling maintains oocyte meiotic arrest in early antral follicles and is suppressed by EGFR-mediated signaling in preovulatory follicles. Molecular reproduction and development 75 22987720
2013 Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene. American journal of medical genetics. Part A 70 24259409
2011 Expression of C-type natriuretic peptide and its receptor NPR-B in cardiomyocytes. Peptides 66 21723350
2007 The receptor guanylyl cyclase Npr2 is essential for sensory axon bifurcation within the spinal cord. The Journal of cell biology 66 17954614
2008 Expression of C-type natriuretic peptide and of its receptor NPR-B in normal and failing heart. Peptides 65 18848850
2015 The Local CNP/GC-B system in growth plate is responsible for physiological endochondral bone growth. Scientific reports 64 26014585
2014 Identification and functional characterization of two novel NPR2 mutations in Japanese patients with short stature. The Journal of clinical endocrinology and metabolism 64 24471569
2014 Reciprocal conversion of Gtr1 and Gtr2 nucleotide-binding states by Npr2-Npr3 inactivates TORC1 and induces autophagy. Autophagy 61 25046117
2015 Heterozygous NPR2 Mutations Cause Disproportionate Short Stature, Similar to Léri-Weill Dyschondrosteosis. The Journal of clinical endocrinology and metabolism 59 26075495
2013 Epidermal growth factor receptor signaling-dependent calcium elevation in cumulus cells is required for NPR2 inhibition and meiotic resumption in mouse oocytes. Endocrinology 54 23787120
2012 A novel loss-of-function mutation in Npr2 clarifies primary role in female reproduction and reveals a potential therapy for acromesomelic dysplasia, Maroteaux type. Human molecular genetics 54 23065701
2002 Vasopressin-dependent inhibition of the C-type natriuretic peptide receptor, NPR-B/GC-B, requires elevated intracellular calcium concentrations. The Journal of biological chemistry 51 12196532
2019 Inhibition of IL-17 ameliorates systemic lupus erythematosus in Roquinsan/san mice through regulating the balance of TFH cells, GC B cells, Treg and Breg. Scientific reports 47 30914691
2016 Whole Genome DNA Methylation Analysis of Obstructive Sleep Apnea: IL1R2, NPR2, AR, SP140 Methylation and Clinical Phenotype. Sleep 43 26888452
2015 Dephosphorylation of juxtamembrane serines and threonines of the NPR2 guanylyl cyclase is required for rapid resumption of oocyte meiosis in response to luteinizing hormone. Developmental biology 43 26522847
2012 NPPC/NPR2 signaling is essential for oocyte meiotic arrest and cumulus oophorus formation during follicular development in the mouse ovary. Reproduction (Cambridge, England) 43 22696190
2017 Natriuretic peptide receptor 2 (NPR2) localized in bovine oocyte underlies a unique mechanism for C-type natriuretic peptide (CNP)-induced meiotic arrest. Theriogenology 39 29080478
2014 Npr2 inhibits TORC1 to prevent inappropriate utilization of glutamine for biosynthesis of nitrogen-containing metabolites. Science signaling 39 25515537
2003 Anticancer drug resistance induced by disruption of the Saccharomyces cerevisiae NPR2 gene: a novel component involved in cisplatin- and doxorubicin-provoked cell kill. Molecular pharmacology 38 12869630
2021 Mechanism of quercetin on the improvement of ovulation disorder and regulation of ovarian CNP/NPR2 in PCOS model rats. Journal of the Formosan Medical Association = Taiwan yi zhi 37 34538551
2014 Bifurcation of axons from cranial sensory neurons is disabled in the absence of Npr2-induced cGMP signaling. The Journal of neuroscience : the official journal of the Society for Neuroscience 36 24431432
2020 NPR2 Variants Are Frequent among Children with Familiar Short Stature and Respond Well to Growth Hormone Therapy. The Journal of clinical endocrinology and metabolism 34 31990356
2004 Down-regulation does not mediate natriuretic peptide-dependent desensitization of natriuretic peptide receptor (NPR)-A or NPR-B: guanylyl cyclase-linked natriuretic peptide receptors do not internalize. Molecular pharmacology 34 15459247
2007 Short-limbed dwarfism: slw is a new allele of Npr2 causing chondrodysplasia. The Journal of heredity 32 17728275
2008 Defective cellular trafficking of missense NPR-B mutants is the major mechanism underlying acromesomelic dysplasia-type Maroteaux. Human molecular genetics 31 18945719
2005 Differential regulation of NPR-B/GC-B by protein kinase c and calcium. Biochemical pharmacology 30 16005434
2004 Sphingosine-1-phosphate inhibits C-type natriuretic peptide activation of guanylyl cyclase B (GC-B/NPR-B). Hypertension (Dallas, Tex. : 1979) 30 15037564
1997 Accumulation of somatic hypermutation and antigen-driven selection in rapidly cycling surface Ig+ germinal center (GC) B cells which occupy GC at a high frequency during the primary anti-hapten response in mice. European journal of immunology 30 9022029
2009 PapR peptide maturation: role of the NprB protease in Bacillus cereus 569 PlcR/PapR global gene regulation. FEMS immunology and medical microbiology 29 19159431
2002 Follicular dendritic cell-signaling molecules required for proliferation and differentiation of GC-B cells. Seminars in immunology 29 12163301
2017 Dephosphorylation of the NPR2 guanylyl cyclase contributes to inhibition of bone growth by fibroblast growth factor. eLife 28 29199951
2009 Expression of guanylyl cyclase (GC)-A and GC-B during brain development: evidence for a role of GC-B in perinatal neurogenesis. Endocrinology 28 19837875
2011 Guanylyl cyclase (GC)-A and GC-B activities in ventricles and cardiomyocytes from failed and non-failed human hearts: GC-A is inactive in the failed cardiomyocyte. Journal of molecular and cellular cardiology 27 22133375
2014 Mutation of Npr2 leads to blurred tonotopic organization of central auditory circuits in mice. PLoS genetics 26 25473838
2015 Acromesomelic dysplasia, type maroteaux caused by novel loss-of-function mutations of the NPR2 gene: Three case reports. American journal of medical genetics. Part A 23 26567084
2014 Epidermal growth factor-network signaling mediates luteinizing hormone regulation of BNP and CNP and their receptor NPR2 during porcine oocyte meiotic resumption. Molecular reproduction and development 23 25348585
2019 Npr2 null mutants show initial overshooting followed by reduction of spiral ganglion axon projections combined with near-normal cochleotopic projection. Cell and tissue research 22 31201541
2021 Clinical Characteristics of Short-Stature Patients With an NPR2 Mutation and the Therapeutic Response to rhGH. The Journal of clinical endocrinology and metabolism 21 33205215
2020 Role of NPR2 mutation in idiopathic short stature: Identification of two novel mutations. Molecular genetics & genomic medicine 21 31960617
1993 Downregulation of C-receptor by natriuretic peptides via ANP-B receptor in vascular smooth muscle cells. The American journal of physiology 21 8238425
2020 Can extracellular vesicles from bovine ovarian follicular fluid modulate the in-vitro oocyte meiosis progression similarly to the CNP-NPR2 system? Theriogenology 20 32814248
2010 Npr2, yeast homolog of the human tumor suppressor NPRL2, is a target of Grr1 required for adaptation to growth on diverse nitrogen sources. Eukaryotic cell 20 20154027
2010 CNP/GC-B system: a new regulator of adipogenesis. Peptides 20 20603173
1998 Expression of mRNA encoding vasopressin V1a, vasopressin V2, and ANP-B receptors in the rat cochlea. Hearing research 19 9557984
1994 Sodium status affects GC-B natriuretic peptide receptor mRNA levels, but not GC-A or C receptor mRNA levels, in the sheep kidney. Clinical science (London, England : 1979) 18 7913429
2020 Short Stature is Progressive in Patients with Heterozygous NPR2 Mutations. The Journal of clinical endocrinology and metabolism 17 32720985
2018 Molecular and in silico analyses validates pathogenicity of homozygous mutations in the NPR2 gene underlying variable phenotypes of Acromesomelic dysplasia, type Maroteaux. The international journal of biochemistry & cell biology 17 30016695
2015 Homozygous sequence variants in the NPR2 gene underlying Acromesomelic dysplasia Maroteaux type (AMDM) in consanguineous families. Annals of human genetics 17 25959430
2008 Reduced ability of C-type natriuretic peptide (CNP) to activate natriuretic peptide receptor B (NPR-B) causes dwarfism in lbab -/- mice. Peptides 17 18554750
2007 Sequencing and cardiac expression of natriuretic peptide receptor 2 (NPR-B) in Sus Scrofa. Peptides 17 17582654
2023 The transcriptional program during germinal center reaction - a close view at GC B cells, Tfh cells and Tfr cells. Frontiers in immunology 16 36817488
2018 Variant proteins stimulate more IgM+ GC B-cells revealing a mechanism of cross-reactive recognition by antibody memory. eLife 16 29709214
2018 Regulation of the Natriuretic Peptide Receptor 2 (Npr2) by Phosphorylation of Juxtamembrane Serine and Threonine Residues Is Essential for Bifurcation of Sensory Axons. The Journal of neuroscience : the official journal of the Society for Neuroscience 16 30249793
2017 Long-term response to growth hormone therapy in a patient with short stature caused by a novel heterozygous mutation in NPR2. Journal of pediatric endocrinology & metabolism : JPEM 15 27941173
2016 Elevated C-type natriuretic peptide elicits exercise preconditioning-induced cardioprotection against myocardial injury probably via the up-regulation of NPR-B. The journal of physiological sciences : JPS 15 27557795
2014 Regulation of hippocampal synaptic plasticity thresholds and changes in exploratory and learning behavior in dominant negative NPR-B mutant rats. Frontiers in molecular neuroscience 15 25520616
2021 Sgpl1 deletion elevates S1P levels, contributing to NPR2 inactivity and p21 expression that block germ cell development. Cell death & disease 14 34083520
2018 GC-B Deficient Mice With Axon Bifurcation Loss Exhibit Compromised Auditory Processing. Frontiers in neural circuits 14 30275816
2018 Loss of Axon Bifurcation in Mesencephalic Trigeminal Neurons Impairs the Maximal Biting Force in Npr2-Deficient Mice. Frontiers in cellular neuroscience 13 29962937
2012 Expression of guanylyl cyclase-B (GC-B/NPR2) receptors in normal human fetal pituitaries and human pituitary adenomas implicates a role for C-type natriuretic peptide. Endocrine-related cancer 13 22645228
2011 Mapping of NPR-B immunoreactivity in the brainstem of Macaca fascicularis. Brain structure & function 13 21455797
2005 Regulation and characterization of two nitroreductase genes, nprA and nprB, of Rhodobacter capsulatus. Applied and environmental microbiology 13 16332736
1997 Detection of C-type natriuretic peptide (CNP) and atrial natriuretic peptide (ANP-B) receptor mRNAs in rat inner ear. Neuroreport 13 9080425
2022 Novel Loss-of-Function Mutations in NPR2 Cause Acromesomelic Dysplasia, Maroteaux Type. Frontiers in genetics 12 35368703
2022 Heterozygous NPR2 Variants in Idiopathic Short Stature. Genes 12 35741827
2016 NPR2 is involved in FSH-mediated mouse oocyte meiotic resumption. Journal of ovarian research 12 26880031
2014 Mutant phenotype analysis suggests potential roles for C-type natriuretic peptide receptor (NPR-B) in male mouse fertility. Reproductive biology and endocrinology : RB&E 12 25012822
2010 NPR-B, the C-type natriuretic peptide specific receptor, is the predominant biological receptor in mouse and pig myocardial tissue. Minerva endocrinologica 12 20595933
1999 Natriuretic peptide receptors, NPR-A and NPR-B, in cultured rabbit retinal pigment epithelium cells. Japanese journal of pharmacology 11 10230865
2024 Phosphatases modified by LH signaling in ovarian follicles: testing their role in regulating the NPR2 guanylyl cyclase†. Biology of reproduction 9 37774352
2021 NPR2 gene variants in familial short stature: a single-center study. Journal of pediatric endocrinology & metabolism : JPEM 9 34565054
2018 Heterozygous NPR2 Mutation in Two Family Members with Short Stature and Skeletal Dysplasia. Case reports in endocrinology 9 30622824
2016 The Loss of Lam2 and Npr2-Npr3 Diminishes the Vacuolar Localization of Gtr1-Gtr2 and Disinhibits TORC1 Activity in Fission Yeast. PloS one 9 27227887
2016 Differential expression and regulation of anti-hypertrophic genes Npr1 and Npr2 during β-adrenergic receptor activation-induced hypertrophic growth in rats. Molecular and cellular endocrinology 9 27283501
2023 Unveiling the pathogenic mechanisms of NPR2 missense variants: insights into the genotype-associated severity in acromesomelic dysplasia and short stature. Frontiers in cell and developmental biology 8 38078000
2022 Novel NPR2 Gene Mutations Affect Chondrocytes Function via ER Stress in Short Stature. Cells 8 35455946
2022 LncRNA-ANAPC2 and lncRNA-NEFM positively regulates the inflammatory response via the miR-451/npr2/ hdac8 axis in grass carp. Fish & shellfish immunology 8 35843524
2020 A novel nonsense mutation in NPR2 gene causing Acromesomelic dysplasia, type Maroteaux in a consanguineous family in Southern Punjab (Pakistan). Genes & genomics 8 32506268
2013 Expression of NPR-B in neurons of the dorsal root ganglia of the rat. Peptides 8 23454171
2010 NPR-B natriuretic peptide receptors in human corneal epithelium: mRNA, immunohistochemistochemical, protein, and biochemical pharmacology studies. Molecular vision 8 20664698
2023 Novel pathogenic NPR2 variants in short stature patients and the therapeutic response to rhGH. Orphanet journal of rare diseases 7 37501190
2021 G protein-coupled estrogen receptor signaling dependent epidermal growth-like factor expression is required for NPR2 inhibition and meiotic resumption in goat oocytes. Theriogenology 7 34571396
2019 Nppc/Npr2/cGMP signaling cascade maintains oocyte developmental capacity. Cellular and molecular biology (Noisy-le-Grand, France) 7 31078160
2017 Effects of gene knockdown of CNP on ventricular remodeling after myocardial ischemia-reperfusion injury through NPRB/Cgmp signaling pathway in rats. Journal of cellular biochemistry 7 28796407
2020 Isolation and characterization of nprB, a novel protease from Streptomyces thermovulgaris. Pakistan journal of pharmaceutical sciences 6 33832913
2017 Suppression of Npr1, not Npr2 gene function induces hypertrophic growth in H9c2 cells in vitro. Biochemical and biophysical research communications 6 28743500
2014 Porcine natriuretic peptide type B (pNPPB) maintains mouse oocyte meiotic arrest via natriuretic peptide receptor 2 (NPR2) in cumulus cells. Molecular reproduction and development 6 24615855