Affinage

NPR3

Atrial natriuretic peptide receptor 3 · UniProt P17342

Length
541 aa
Mass
59.8 kDa
Annotated
2026-06-10
86 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NPR3 (NPR-C) is the natriuretic peptide clearance receptor whose loss-of-function in vivo de-represses local CNP/ANP/cGMP signaling, establishing it as a tonic limiter of natriuretic peptide availability across skeletal, cardiovascular, and developmental tissues (PMID:10468599, PMID:30032985, PMID:11788435). Beyond clearance, its 17-amino acid intracellular middle-region domain (R469–R485) is necessary and sufficient to activate Gi1/Gi2, inhibit adenylyl cyclase, and stimulate PLC-β via βγ subunits, with N- and C-terminal basic residues required for activity and the distal C-terminus exerting autoinhibition (PMID:10364194, PMID:12676657). Through this Gi coupling, NPR-C inhibits L-type Ca2+ current in sinoatrial node myocytes and hypothalamic magnocellular neurons to slow heart rate and modulate neurosecretion (PMID:14704228, PMID:15772242), and the receptor ectodomain binds hormone with a 1:2 hormone-to-receptor stoichiometry that drives a membrane-proximal conformational change (PMID:15911071). Biallelic human loss-of-function mutations cause tall stature, long digits, and aortic dilatation accompanied by reduced NTproNP/NP ratios and elevated cGMP, mirroring the skeletal overgrowth of mouse Npr3 alleles and confirming clearance-receptor function in humans (PMID:10468599, PMID:27959934, PMID:30032985). In disease contexts NPR-C deletion is protective or pathogenic depending on tissue: it limits atrial fibrosis and arrhythmogenic remodeling and regulates autonomic heart-rate control (PMID:30636477, PMID:29242602), attenuates diabetic cardiac and kidney fibrosis through cAMP/PKA–cGMP/PKG signaling, TGIF1-mediated suppression of Smad2/3, and altered TGF-βR2 trafficking (PMID:37531438, PMID:40557490), and reduces atherosclerotic burden via cAMP/PKA-driven AKT1 activation and NF-κB suppression (PMID:37553374). NPR-C also acts through non-canonical partners independent of clearance: it recruits the deubiquitinase USP30 to stabilize C/EBPβ and promote hepatic steatosis (PMID:39433172), scaffolds raptor to inhibit mTORC1 in vascular smooth muscle as the receptor for musclin (PMID:39632658, PMID:41074587), and in vascular smooth muscle restrains an ERK1/2–PPARγ–HADHB axis that protects against aortic dissection (PMID:40377018).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1999 High

    Established that the short NPR-C cytoplasmic tail is itself a signaling module, defining the precise sequence that couples the receptor to heterotrimeric G proteins rather than merely clearing ligand.

    Evidence Synthetic peptide fragments of the NPR-C cytoplasmic domain in G protein binding, adenylyl cyclase, PLC, and smooth muscle contraction assays

    PMID:10364194

    Open questions at the time
    • Did not test the activating domain in the context of the full-length receptor
    • G protein selectivity beyond Gi1/Gi2 not resolved
  2. 1999 Medium

    Showed that NPR-C signaling has functional neuromodulatory output, localizing a dopamine-secretion-suppressing activity to the proximal cytoplasmic domain.

    Evidence Receptor-derived peptides and blocking antibodies delivered into permeabilized PC12 cells with dopamine efflux readout

    PMID:10067834

    Open questions at the time
    • Single lab, single method
    • Exact effector linking peptide to dopamine efflux not identified
  3. 1999 High

    Genetically established NPR-C as an in vivo brake on bone growth, answering whether the clearance receptor has a non-redundant physiological role.

    Evidence Three independent mouse skeletal-overgrowth alleles mapped by positional cloning to Npr3

    PMID:10468599

    Open questions at the time
    • Did not establish which natriuretic peptide accumulates to drive overgrowth
    • Did not distinguish clearance from signaling contribution
  4. 2003 High

    Refined the G protein-activating domain to single residues, establishing necessity and sufficiency of R469–R485 and identifying a distal autoinhibitory segment.

    Evidence Site-directed and deletion mutagenesis of rat NPR-C with Gi, PLC-β, and adenylyl cyclase assays

    PMID:12676657

    Open questions at the time
    • Structural basis of autoinhibition not resolved
    • Conformational coupling from ectodomain to this tail unproven
  5. 2004 High

    Connected NPR-C/Gi coupling to a concrete cardiac electrophysiological output, showing it reduces L-type Ca2+ current in pacemaker cells to slow heart rate.

    Evidence Voltage-clamp of isolated SA node myocytes with intracellular Gi-activator peptide dialysis and Langendorff ECG

    PMID:14704228

    Open questions at the time
    • Downstream effector between Gi and ICa(L) not defined
    • If current spared, leaving full pacemaker mechanism incomplete
  6. 2005 High

    Extended NPR-C Gi-coupled ICa(L) inhibition to central neurons, generalizing the signaling mechanism beyond cardiac tissue.

    Evidence Whole-cell patch-clamp of hypothalamic magnocellular neurons with Gi-activator peptide dialysis

    PMID:15772242

    Open questions at the time
    • Physiological neurosecretory consequence not directly measured
    • T-type channels unaffected, selectivity mechanism unexplained
  7. 2005 High

    Provided the structural logic of ligand recognition, showing a 1:2 hormone:receptor stoichiometry and an allosteric conformational change in the ectodomain.

    Evidence X-ray crystallography of NPR-C ectodomain in quiescent and hormone-bound states

    PMID:15911071

    Open questions at the time
    • No structure of the intracellular signaling domain
    • How ectodomain change propagates to the cytoplasmic activating domain unknown
  8. 2006 Medium

    Established tissue-specific NPR-C signaling outputs (NOS activation, PLC-driven exocrine secretion) confirmed by pertussis toxin sensitivity, broadening the Gi-coupled effector repertoire.

    Evidence Selective agonist pharmacology, pertussis toxin, and enzyme/second-messenger assays in pancreatic acini, kidney, aorta, and heart

    PMID:15959462 PMID:16712979 PMID:17702953

    Open questions at the time
    • Single-lab pharmacology without genetic loss-of-function
    • Direct molecular link from Gi to NOS not reconstituted
  9. 2016 High

    Provided allelic and pathway resolution of the clearance function, showing ER-retained NPR3 raises CNP availability for NPR2 and elevates p38 MAPK in chondrocytes.

    Evidence ENU Tyr209Asn mouse mutation, COS-7 expression localization, and growth-plate p38 phospho-immunohistochemistry

    PMID:27959934

    Open questions at the time
    • Did not quantify circulating versus local CNP
    • Contribution of NPR-C's own signaling versus clearance to growth-plate phenotype unresolved
  10. 2018 High

    Established NPR3 as a human Mendelian disease gene, linking biallelic loss-of-function to a skeletal-aortic syndrome with biochemical evidence of impaired peptide clearance.

    Evidence Whole-exome sequencing of three families with in vitro localization assays and plasma NTproNP/NP and cGMP measurements

    PMID:30032985

    Open questions at the time
    • Aortic dilatation mechanism not dissected
    • Did not test signaling-domain-specific contribution to phenotype
  11. 2017 High

    Demonstrated that NPR-C controls autonomic heart-rate regulation in vivo, beyond direct ion-channel effects.

    Evidence Telemetric ECG, heart-rate variability analysis, and autonomic pharmacology in NPR-C knockout mice

    PMID:29242602

    Open questions at the time
    • Site of autonomic action (central versus peripheral) not defined
    • Molecular effector for autonomic shift not identified
  12. 2019 High

    Established NPR-C as a modulator of atrial structural and electrical remodeling, with agonist rescue indicating therapeutic tractability.

    Evidence Angiotensin II challenge in NPR-C knockout mice with optical mapping, patch clamp, fibrosis quantification, and cANF rescue

    PMID:30636477

    Open questions at the time
    • Cell-type responsible for antifibrotic effect not isolated
    • Signaling pathway linking NPR-C to fibrosis not defined in this study
  13. 2023 High

    Defined the antifibrotic and atheroprotective signaling chains of NPR-C loss, implicating cAMP/PKA–cGMP/PKG, TGIF1-mediated Smad2/3 suppression, and AKT1/NF-κB axes.

    Evidence NPRC knockout and endothelial-specific knockout/overexpression in diabetic and ApoE-/- mouse models with RNA-seq and pathway Western blots

    PMID:37531438 PMID:37553374

    Open questions at the time
    • Whether effects reflect clearance versus receptor signaling not fully separated
    • Direct molecular target coupling NPR-C to cAMP/PKA in these tissues not pinpointed
  14. 2024 High

    Revealed a clearance-independent scaffolding function, showing NPR-C recruits USP30 to deubiquitinate and stabilize C/EBPβ and drive hepatic steatosis.

    Evidence Proteomics, Co-IP, and site-specific ubiquitination mapping of the NPRC–USP30–C/EBPβ complex

    PMID:39433172

    Open questions at the time
    • Whether ligand binding regulates USP30 recruitment unknown
    • Structural basis of NPR-C ANPR domain–USP30 interaction undefined
  15. 2024 Medium

    Identified NPR-C as the receptor mediating musclin's anti-proliferative effects and as a raptor-recruiting scaffold that inhibits mTORC1 in vascular smooth muscle.

    Evidence Co-IP of musclin–NPR3 and NPR3–raptor with siRNA silencing and mTORC1/glycolysis functional rescue in PASMCs and VSMCs

    PMID:39632658 PMID:41074587

    Open questions at the time
    • Co-IP without reciprocal structural validation
    • Single lab; whether raptor recruitment requires ligand binding unknown
  16. 2025 High

    Extended NPR-C disease mechanisms to kidney and aorta, defining TGF-βR2 trafficking control in podocytes and an ERK1/2–PPARγ–HADHB metabolic axis in vascular smooth muscle.

    Evidence Podocyte- and VSMC-specific NPRC knockout mice with mass spectrometry, RNA-seq, trafficking assays, and pharmacological rescue

    PMID:40377018 PMID:40557490

    Open questions at the time
    • How NPR-C controls TGF-βR2 recycling mechanistically not resolved
    • Whether ERK1/2 activation is direct or secondary to altered peptide clearance unclear
  17. 2025 Medium

    Linked adipocyte NPR-C to cardiac remodeling through a secreted Wnt5a signal, defining an inter-organ axis in HFpEF.

    Evidence Adipocyte- and cardiomyocyte-specific Nprc knockout mice in a HFpEF model with adipose RNA-seq and LGK974 rescue (preprint)

    PMID:bio_10.1101_2025.10.29.685456

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Mechanism linking NPR-C to Wnt5a transcription undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the ectodomain conformational change is allosterically transmitted to the cytoplasmic R469–R485 activating domain, and how a single short tail selects among Gi coupling, USP30 recruitment, raptor scaffolding, and TGF-βR2 trafficking in different cell types.
  • No full-length receptor structure with intracellular domain
  • Determinants of partner selection across tissues unknown
  • Clearance versus signaling contributions to each phenotype not cleanly separated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 4 GO:0060089 molecular transducer activity 4 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1430728 Metabolism 3 R-HSA-1474244 Extracellular matrix organization 3
Partners
C/EBPBETAGI1GI2MUSCLINNMBRRPTORTGFBR2USP30

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 The 17-amino acid middle-region peptide (Arg469–Arg485) of the NPR-C intracellular domain selectively binds Gi1 and Gi2, activates phospholipase C-β3 via βγ subunits, and inhibits adenylyl cyclase, identifying this sequence as the G protein-activating domain. A C-terminal BB-XX-B motif within this peptide mediates G protein binding but not activation. Synthetic peptide fragments of NPR-C cytoplasmic domain used in binding assays, adenylyl cyclase inhibition assays, PLC activity assays, and smooth muscle contraction assays The Journal of biological chemistry High 10364194
2003 Mutational and deletion analysis of rat NPR-C confirmed that the 17-amino acid sequence R469–R485 in the middle region of the intracellular domain is both necessary and sufficient for G protein (Gi1/Gi2) and PLC-β activation and adenylyl cyclase inhibition. Substitution of N-terminal arginines (R469/R470) or C-terminal basic residues (H481, R482, R485) abolished activity. The 11 C-terminal residues (E486–A496) serve an autoinhibitory function. Site-directed mutagenesis and deletion mutagenesis of NPR-C intracellular domain expressed in cells; Gi1/Gi2 activity assays, PLC-β assay, adenylyl cyclase inhibition assay American journal of physiology. Cell physiology High 12676657
2004 CNP and the selective NPR-C agonist cANF both significantly inhibit L-type Ca2+ current (ICa(L)) in sinoatrial node myocytes. Dialysis of a 17-amino acid Gi-activator peptide derived from NPR-C intracellular domain reproduced this inhibition, demonstrating that NPR-C couples to Gi to reduce ICa(L) and decrease heart rate. The hyperpolarization-activated current (If) was unaffected. Voltage-clamp electrophysiology on isolated SA node myocytes; intracellular dialysis of NPR-C-derived Gi-activator peptide; Langendorff-perfused heart ECG American journal of physiology. Heart and circulatory physiology High 14704228
2005 CNP and cANF inhibit L-type Ca2+ current (~50%) and reduce action potential firing in magnocellular neurosecretory cells (MNCs) of the hypothalamus via NPR-C coupled to Gi protein, as demonstrated by mimicry with an intracellular Gi-activator peptide. T-type Ca2+ channels were unaffected. Whole-cell patch-clamp recordings in acutely isolated MNCs and slice preparation; intracellular dialysis of Gi-activator peptide Journal of neurophysiology High 15772242
2005 Crystal structure of the NPR-C extracellular domain reveals a 1:2 hormone-to-receptor stoichiometry where the hormone intercalates at the interface of a receptor dimer, inducing a large-scale conformational change in membrane-proximal regions. This allosteric mechanism of hormone recognition is proposed to be conserved across the NPR family. X-ray crystallography of NPR-C ectodomain in quiescent and hormone-bound forms Peptides High 15911071
1999 Three independent allelic mutations (lgj, stri, lgj2J) in mice that cause skeletal overgrowth (extended endochondral proliferation zone, elongated body) all map to and disrupt the Npr3 gene, establishing NPR-C as a required component of the natriuretic peptide clearance pathway that limits bone growth in vivo. Genetic mapping, allelism testing, skeletal preparation analysis, candidate gene identification by positional cloning Proceedings of the National Academy of Sciences of the United States of America High 10468599
2016 An ENU-induced Tyr209Asn missense mutation in NPR3 introduces an aberrant N-linked glycosylation site, causing the protein to be retained in the endoplasmic reticulum and absent from the plasma membrane. Loss of plasma membrane NPR3 increases CNP availability for NPR2, elevating MAPK (p38) signaling in growth plate chondrocytes, expanding hypertrophic zones, and causing kyphosis with vertebral elongation. ENU mutagenesis screen; expression of wild-type and mutant NPR3 in COS-7 cells; immunohistochemistry for p38 MAPK phosphorylation; histomorphometric analysis of growth plates PloS one High 27959934
2018 Bi-allelic loss-of-function mutations in NPR3 in humans (missense mutations p.Ser148Pro and p.Asp363Val causing intracellular retention; nonsense p.Tyr508* causing NMD) result in tall stature, long digits, extra epiphyses, and aortic dilatation. Biochemical analysis showed a reduced NTproNP/NP ratio and high cGMP, consistent with reduced natriuretic peptide clearance and consequent increased NPR-A/B signaling. Whole-exome sequencing; in vitro expression of mutant NPR-C to assess plasma membrane localization; plasma biochemistry (NTproNP/NP ratios, cGMP) American journal of human genetics High 30032985
1999 A pentadecapeptide from the cytoplasmic region of NPR-C (closest to the membrane) suppressed calcium-evoked dopamine efflux ~40% in permeabilized PC12 cells, mimicking natriuretic peptide action. An antibody against this fragment abolished the neuromodulatory effect of CNP, and the C-terminal nonadecapeptide was inactive, localizing the neuromodulatory function to the proximal cytoplasmic domain. Intracellular delivery of receptor-derived peptides and antibodies in digitonin-permeabilized PC12 cells; dopamine efflux assay Endocrinology Medium 10067834
2003 ANP stimulates exocrine pancreatic secretion in rats via NPR-C receptors (mimicked by cANP4-23) coupled to phosphoinositide hydrolysis (PLC pathway), not cAMP. The PLC inhibitor U-73122 blocked ANF-evoked phosphoinositide hydrolysis. Cholinergic, adrenergic, and nitric oxide pathways were not involved. In vivo pancreatic secretion in anesthetized rats with selective agonists; phosphoinositide hydrolysis assay in isolated acini; pharmacological blockade studies American journal of physiology. Gastrointestinal and liver physiology Medium 12829435
2006 CNP stimulates amylase release from isolated pancreatic acini specifically through NPR-C (mimicked by cANP4-23, blocked by pertussis toxin), acting via the PLC pathway and IP3 receptors, not via cAMP or PKG. Higher CNP concentrations also reduced cAMP and increased cGMP, engaging NPR-A/B. Amylase secretion assay in isolated pancreatic acini with selective agonists/antagonists; PLC inhibitor (U-73122); IP3 receptor antagonist (2-APB); cAMP and cGMP measurement; pertussis toxin treatment American journal of physiology. Gastrointestinal and liver physiology Medium 17702953
2006 ANP/cANP4-23 activation of NPR-C in kidney, aorta, heart, and atria increases NOS activity via Gi (blocked by pertussis toxin) and Ca2+-dependent calmodulin pathways (blocked by nifedipine and calmidazolium). In the atria, NPR-C appears to be the primary mediator of ANP-stimulated NOS activation. NOS activity assay (L-[14C]-arginine) in rat kidney, aorta, and heart; pharmacological blockade with pertussis toxin, nifedipine, calmidazolium Regulatory peptides Medium 16712979
2006 NPR-C receptor localizes throughout porcine basilar artery including intramural nerves, and its activation produces NO-dependent vasodilation that is independent of the endothelium, implying NPR-C stimulates nNOS in intramural nerves to mediate vasodilation. Immunocytochemistry for receptor localization; vascular pharmacology with selective agonists; NOS inhibition (L-NAME); endothelial denudation Journal of cerebral blood flow and metabolism Medium 15959462
2001 FGF-1, FGF-2, and PDGF-BB reduce NPR-C mRNA expression in pulmonary arterial smooth muscle cells via activation of tyrosine kinase receptors and MEK/ERK signaling (blocked by PD-166866, U-0126, and PD-98059), whereas hypoxia per se, Ang II, ET-1, ANP, and cGMP do not reduce NPR-C mRNA. Northern blot analysis of NPR-C mRNA in growth-arrested rat PASMCs treated with growth factors, kinase inhibitors, and other stimuli American journal of physiology. Lung cellular and molecular physiology Medium 11404258
2001 In human thyrocytes, NPR-C (>97% of ANF binding sites) unexpectedly increases intracellular cAMP upon activation by ANP or cANF, contrasting with its canonical inhibitory coupling. This stimulatory cAMP response is absent in cells grown in low serum without pituitary/hypothalamic extracts. Radioligand binding (125I-ANF); cAMP measurement in human thyrocyte (HTU-5) cells with selective NPR-C agonist cANF; comparison with rat aortic smooth muscle cells Regulatory peptides Medium 11164945
2011 NPR-C knockdown in murine embryonic stem cells causes apoptosis accompanied by induction of p53 protein. Chemical inhibition of p53 reduces apoptosis in NPR-C-deficient cells. Activation of NPR-C with cANF4-23 protects ES cells against oxidative stress-induced apoptosis by blocking p53 activation and Nanog suppression. siRNA knockdown of NPR-C; flow cytometry for apoptosis; Western blot for p53; p53 inhibitor α-pifithrin rescue experiment; cANF4-23 agonist treatment with oxidative stress challenge Stem cells and development Medium 21846177
2016 NPR3 knockdown in H9C2 cardiomyocytes increases caspase-3, -8, and -9 activities, upregulates BRCA1 expression with predominantly cytoplasmic localization, increases CREB activity (positive regulator of BRCA1), and elevates TNF-α, activating both intrinsic and extrinsic apoptotic pathways. This identifies NPR3 as a suppressor of cardiomyocyte apoptosis acting through BRCA1 and TNF-α. Stable shRNA knockdown of NPR3 in H9C2 cells; caspase activity assays; Western blot and immunofluorescence for BRCA1 localization; CREB activity assay; TNF-α mRNA quantification Cell cycle (Georgetown, Tex.) Medium 27494651
2002 Dietary salt supplementation selectively downregulates NPR-C mRNA by >60% in kidney (but not lung, brain, or heart) of both ANP+/+ and ANP-/- mice, demonstrating that this regulation is ANP-independent, and is accompanied by increased renal cGMP, suggesting local elevation of natriuretic peptide activity. Northern blot for NPR-C mRNA in multiple organs; cGMP measurement; comparison of ANP knockout vs wild-type mice on normal vs high-salt diets American journal of physiology. Renal physiology Medium 11788435
2004 cAMP elevation (by forskolin or dibutyryl-cAMP) significantly increases NPR-C transcript levels in human aortic smooth muscle cells via a PKA-dependent mechanism (blocked by KT-5720), with functional upregulation confirmed by increased 125I-ANF binding competed by the NPR-C-specific ligand C-ANF(4-23). qRT-PCR; pharmacological activation/inhibition of cAMP/PKA pathway; radioligand binding assay Molecular and cellular endocrinology Medium 15149737
2019 NPR-C knockout mice treated with angiotensin II show exacerbated atrial fibrillation susceptibility, prolonged action potential duration, reduced Vmax, and substantially greater atrial fibrosis compared to wild-type. NPR-C agonist cANF dose-dependently reduces AF inducibility and prevents Ang II-induced atrial electrophysiological changes and fibrosis, identifying NPR-C as a modulator of atrial structural and electrical remodeling. In vivo electrophysiology, high-resolution optical mapping, patch clamp, molecular biology in NPR-C-/- mice and wild-type mice ± Ang II ± cANF Circulation. Arrhythmia and electrophysiology High 30636477
2017 NPR-C knockout mice exhibit elevated heart rate, reduced heart rate variability, enhanced arrhythmogenesis (sinus pauses), and decreased parasympathetic/increased sympathetic tone as assessed by HRV analysis and autonomic pharmacology (atropine/propranolol), establishing NPR-C as a regulator of autonomic control of heart rate. Telemetric ECG recording in awake mice; heart rate variability analysis (time and frequency domain); pharmacological autonomic blockade Scientific reports High 29242602
2023 NPRC deletion in diabetic mice attenuates cardiac fibrosis by upregulating TGIF1 (which inhibits Smad2/3 phosphorylation), mediated by activation of cAMP/PKA and cGMP/PKG signaling downstream of NPRC deletion. NPRC knockdown in cardiac fibroblasts decreases collagen synthesis and proliferation. NPRC-/- diabetic mouse model; RNA sequencing; Western blot for Smad2/3 phosphorylation and TGIF1; in vitro knockdown in cardiac fibroblasts and cardiomyocytes Science advances High 37531438
2023 NPRC deletion reduces atherosclerotic lesion size and instability in ApoE-/- mice. Mechanistically, NPRC deletion activates cAMP/PKA signaling, leading to upregulated AKT1 pathway and downregulated NF-κB pathway, reducing ROS, inflammation, and endothelial apoptosis while increasing eNOS expression. Endothelial cell-specific NPRC knockout recapitulates the protective effect, while endothelial overexpression aggravates lesions. Systemic and endothelial cell-specific NPRC KO in ApoE-/- mice; endothelial overexpression model; in vitro HAEC knockdown/overexpression; ROS, cytokine, NF-κB, AKT, eNOS pathway assays Signal transduction and targeted therapy High 37553374
2021 NPRC (Npr3) in spinal dorsal horn neurons co-expresses with NMBR (neuromedin B receptor). BNP facilitates NMB-encoded histaminergic itch through a NPRC–NMBR cross-signaling mechanism: NPRC is required for histamine-evoked itch but not chloroquine-evoked itch, and BNP evokes Ca2+ responses in cells co-expressing NMBR and NPRC, suggesting NPRC signals via the Gq-PLC-Ca2+ pathway through NMBR crosstalk. In situ hybridization for co-localization; behavioral itch assays in Npr3 KO mice; Ca2+ imaging in NMBR/NPRC HEK293 cells and dorsal horn neurons eLife High 34919054
2023 In Xenopus, Npr3 regulates neural crest (NC) and cranial placode (CP) progenitor formation through dual functions: (1) as a clearance receptor that modulates local natriuretic peptide concentrations for optimal cGMP production through Npr1 activation, and (2) as a signaling receptor that controls cAMP levels through inhibition of adenylyl cyclase, with differential regulation of NC vs. CP developmental programs. Morpholino-based knockdowns of Npr3, Npr1, Nppa, Nppc in Xenopus; pharmacological inhibitors; rescue assays; in situ hybridization eLife High 37162198
2016 In Npr3-deficient mice, a small population (~13%) of dorsal root ganglion axons fail to form T-like bifurcation branches, suggesting Npr3 expressed by cells associated with dorsal roots (not DRG neurons themselves) contributes to normal sensory axon branching as a scavenger/clearance receptor regulating local CNP/cGMP levels. In situ hybridization, immunohistology, real-time cGMP imaging with fluorescent sensor, axon tracking in Npr3-deficient mice The European journal of neuroscience Medium 27740716
2020 miR-146a directly targets NPR3 in adipocytes. CRISPR/Cas9-mediated knockout of NPR3 increases insulin-stimulated glucose uptake and enhances de novo lipogenesis in human SGBS adipocytes, identifying NPR3 as a functional downstream mediator of miR-146a in regulating adipocyte insulin sensitivity. miR-146a-/- mice on high-fat diet; miRNA mimic/inhibitor transfection; CRISPR/Cas9 KO of NPR3; glucose uptake assays; lipogenesis assays in SGBS adipocytes Cellular and molecular life sciences High 33206203
2021 NPR3 overexpression in osteosarcoma cells inhibits PI3K/AKT pathway activity. NPR3 downregulation activates PI3K/AKT, promoting proliferation; this effect is reversed by PI3K/AKT pathway blockade. The transcription factor POU2F1 suppresses NPR3 promoter activity by binding the −900 to −800 bp region, reducing NPR3 expression. NPR3 overexpression and knockdown in OS cell lines; cell viability, cell cycle, apoptosis assays; Western blot for PI3K/AKT; dual-luciferase reporter and site-directed mutagenesis of NPR3 promoter; xenograft tumor experiments Cellular signalling Medium 34229087
2024 NPRC promotes hepatic steatosis by recruiting the deubiquitinase USP30 via its ANPR domain; USP30 then deubiquitinates C/EBPβ at K149 (removing K48-linked polyubiquitin chains), stabilizing C/EBPβ and driving excessive lipid accumulation. The C/EBPβ DNA-binding domain interacts with USP30. Proteomic analysis, ubiquitination assay, Co-IP for NPRC-USP30 and USP30-C/EBPβ interactions, MeRIP; site-specific ubiquitination mapping Metabolism: clinical and experimental High 39433172
2025 NPRC deficiency in podocytes reduces recycling and increases degradation of TGF-β receptor 2 (TGF-βR2), thereby suppressing TGF-β1/Smad2/3 signaling and attenuating glomerular fibrosis and podocyte injury in diabetic kidney disease. Podocyte-specific NPRC knockout mice showed reduced collagen synthesis and improved renal function. Podocyte-specific NPRC KO mice in diabetic model; mass spectrometry; ELISA; Western blot for Smad2/3 phosphorylation, TGF-βR2 expression and recycling; histological analysis Circulation research High 40557490
2025 NPR-C deficiency in vascular smooth muscle cells (VSMC-specific KO) triggers thoracic aortic dissection under angiotensin II plus high-salt diet. Mechanistically, NPR-C loss activates ERK1/2, which reduces PPARγ expression and activity, downregulating HADHB (a mitochondrial trifunctional protein subunit for fatty acid oxidation), impairing mitochondrial homeostasis, and promoting extracellular matrix degeneration and VSMC apoptosis. VSMC-specific and endothelial cell-specific NPR-C KO mice; RNA-sequencing; Western blot for ERK1/2, PPARγ, HADHB; NPR-C agonist C-ANP4-23 treatment; spermidine (MTP activator) rescue Cardiovascular research High 40377018
2024 Musclin binds NPR3 in pulmonary arterial smooth muscle cells, and NPR3 silencing reverses musclin-mediated inhibition of AKT phosphorylation and mTORC1 activity, glycolysis, oxidative stress, proliferation, and migration, establishing NPR3 as the receptor through which musclin exerts its protective anti-proliferative effects in PASMCs. Co-IP for musclin-NPR3 interaction; NPR3 siRNA silencing; mTORC1 activity assay; ECAR glycolysis assay; cell proliferation and migration assays in PASMCs Acta biochimica et biophysica Sinica Medium 39632658
2025 Musclin induces NPR3–raptor interaction, which inhibits mTORC1 activity in VSMCs. NPR3 silencing abolishes musclin-mediated suppression of mTORC1, glycolysis, and VSMC phenotypic switching, establishing NPR3 as a scaffold that recruits raptor to inhibit mTORC1 and prevent vascular intimal hyperplasia. Co-IP for NPR3-raptor interaction; AAV6-mediated musclin overexpression in mouse vascular IH model; NPR3 siRNA; ECAR assay; VSMC differentiation marker expression Acta biochimica et biophysica Sinica Medium 41074587
2025 In osteosarcoma cells, the E3 ubiquitin ligase UBE4A promotes ubiquitination and proteasomal degradation of NPR3 (a tumor suppressor). IGF2BP3 stabilizes UBE4A mRNA via m6A modification recognition, thereby indirectly reducing NPR3 levels and promoting OS malignancy. NPR3 overexpression reverses UBE4A-driven proliferation. RIP, MeRIP, RNA decay assays for IGF2BP3-UBE4A mRNA interaction; cell viability/apoptosis assays; Western blot; Co-IP/ubiquitination assay for UBE4A-NPR3 Physiology international Medium 40674149
2022 NPR3 downregulation in osteosarcoma activates MAPK pathway (p38 MAPK and Erk1/2), impairing osteogenic differentiation of periodontal ligament stem cells under high glucose conditions. Inhibition of the NPR3-mediated p38 MAPK or Erk1/2 pathway enhances osteogenic differentiation. RNA-seq; lentivirus transfection for NPR3 modulation; Western blot for MAPK pathways; ALP staining/activity; Alizarin Red quantification; osteogenic differentiation assays Stem cell research & therapy Medium 35841070
2025 NPR3 inhibits dental pulp stem cell (DPSC) colony formation, migration, and differentiation by positively regulating ERK1/2 phosphorylation. Ligustrazine (TMP) was identified as an NPR3 inhibitor, promoting DPSC functions; NPR3 overexpression or ERK1/2 inhibitor treatment abrogated TMP effects. NPR3 overexpression and knockdown in DPSCs; colony formation, migration, differentiation assays; Western blot for ERK1/2 phosphorylation; high-throughput drug screening; rescue experiments Experimental cell research Medium 39984110
2025 In adipocyte-specific Nprc (Npr3) knockout mice subjected to HFpEF induction, adipocyte Nprc loss downregulates Wnt5a expression in visceral adipose tissue. Wnt5a exposure causes cardiomyocyte hypertrophy in vitro, and in vivo inhibition of Wnt ligand secretion (LGK974) reduces circulating Wnt5a and improves cardiac remodeling, identifying an adipocyte Nprc → Wnt5a → cardiomyocyte axis in HFpEF. Adipocyte-specific and cardiomyocyte-specific Nprc KO mice; 2-hit HFpEF model; echocardiography; bulk RNA-seq of adipose tissue; H9C2 Wnt5a treatment; in vivo LGK974 treatment bioRxivpreprint Medium bio_10.1101_2025.10.29.685456

Source papers

Stage 0 corpus · 86 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 NPR3 and NPR4 are receptors for the immune signal salicylic acid in plants. Nature 664 22699612
2018 Opposite Roles of Salicylic Acid Receptors NPR1 and NPR3/NPR4 in Transcriptional Regulation of Plant Immunity. Cell 525 29656896
2017 Long noncoding RNA MRCCAT1 promotes metastasis of clear cell renal cell carcinoma via inhibiting NPR3 and activating p38-MAPK signaling. Molecular cancer 186 28659173
2020 Diverse Roles of the Salicylic Acid Receptors NPR1 and NPR3/NPR4 in Plant Immunity. The Plant cell 135 33037144
1999 Three new allelic mouse mutations that cause skeletal overgrowth involve the natriuretic peptide receptor C gene (Npr3). Proceedings of the National Academy of Sciences of the United States of America 111 10468599
1999 Identification of the G protein-activating domain of the natriuretic peptide clearance receptor (NPR-C). The Journal of biological chemistry 92 10364194
2011 Selective regulation of autophagy by the Iml1-Npr2-Npr3 complex in the absence of nitrogen starvation. Molecular biology of the cell 79 21900499
2023 NPRC deletion attenuates cardiac fibrosis in diabetic mice by activating PKA/PKG and inhibiting TGF-β1/Smad pathways. Science advances 75 37531438
2014 Reciprocal conversion of Gtr1 and Gtr2 nucleotide-binding states by Npr2-Npr3 inactivates TORC1 and induces autophagy. Autophagy 61 25046117
2003 Identification of the G protein-activating sequence of the single-transmembrane natriuretic peptide receptor C (NPR-C). American journal of physiology. Cell physiology 60 12676657
2019 NPR-C (Natriuretic Peptide Receptor-C) Modulates the Progression of Angiotensin II-Mediated Atrial Fibrillation and Atrial Remodeling in Mice. Circulation. Arrhythmia and electrophysiology 56 30636477
2010 NPR-C: a component of the natriuretic peptide family with implications in human diseases. Journal of molecular medicine (Berlin, Germany) 56 20563546
2023 NPRC deletion mitigated atherosclerosis by inhibiting oxidative stress, inflammation and apoptosis in ApoE knockout mice. Signal transduction and targeted therapy 51 37553374
2018 Long Noncoding RNA BCYRN1 Promotes the Proliferation of Colorectal Cancer Cells via Up-Regulating NPR3 Expression. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 49 30114690
2004 Effects of C-type natriuretic peptide on ionic currents in mouse sinoatrial node: a role for the NPR-C receptor. American journal of physiology. Heart and circulatory physiology 48 14704228
2016 Salicylic Acid Regulates Pollen Tip Growth through an NPR3/NPR4-Independent Pathway. Molecular plant 36 27575693
2006 Location and function of VPAC1, VPAC2 and NPR-C receptors in VIP-induced vasodilation of porcine basilar arteries. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 35 15959462
2022 UBP12/UBP13-mediated deubiquitination of salicylic acid receptor NPR3 suppresses plant immunity. Molecular plant 32 36415131
2020 miR-146a regulates insulin sensitivity via NPR3. Cellular and molecular life sciences : CMLS 32 33206203
2020 LncRNA FENDRR Upregulation Promotes Hepatic Carcinoma Cells Apoptosis by Targeting miR-362-5p Via NPR3 and p38-MAPK Pathway. Cancer biotherapy & radiopharmaceuticals 30 32251605
2015 Natriuretic peptide receptor 3 (NPR3) is regulated by microRNA-100. Journal of molecular and cellular cardiology 30 25736855
2018 Bi-allelic Loss-of-Function Mutations in the NPR-C Receptor Result in Enhanced Growth and Connective Tissue Abnormalities. American journal of human genetics 29 30032985
2003 Atrial natriuretic factor stimulates exocrine pancreatic secretion in the rat through NPR-C receptors. American journal of physiology. Gastrointestinal and liver physiology 29 12829435
2006 Role of NPR-C natriuretic receptor in nitric oxide system activation induced by atrial natriuretic peptide. Regulatory peptides 27 16712979
2022 Metformin combats high glucose-induced damage to the osteogenic differentiation of human periodontal ligament stem cells via inhibition of the NPR3-mediated MAPK pathway. Stem cell research & therapy 23 35841070
2011 Impact of natriuretic peptide clearance receptor (NPR3) gene variants on blood pressure in type 2 diabetes. Diabetes care 23 21464461
2021 NPR3, transcriptionally regulated by POU2F1, inhibits osteosarcoma cell growth through blocking the PI3K/AKT pathway. Cellular signalling 22 34229087
2021 BNP facilitates NMB-encoded histaminergic itch via NPRC-NMBR crosstalk. eLife 21 34919054
2016 Dorsal root ganglion axon bifurcation tolerates increased cyclic GMP levels: the role of phosphodiesterase 2A and scavenger receptor Npr3. The European journal of neuroscience 20 27740716
2001 Tyrosine kinase receptor activation inhibits NPR-C in lung arterial smooth muscle cells. American journal of physiology. Lung cellular and molecular physiology 19 11404258
2001 Natriuretic peptides increase cAMP production in human thyrocytes via the natriuretic peptide clearance receptor (NPR-C). Regulatory peptides 18 11164945
2016 NPR3 protects cardiomyocytes from apoptosis through inhibition of cytosolic BRCA1 and TNF-α. Cell cycle (Georgetown, Tex.) 17 27494651
2006 Identification, regulation and anti-proliferative role of the NPR-C receptor in gastric epithelial cells. Molecular and cellular biochemistry 17 16786190
2005 C-type natriuretic peptide inhibits L-type Ca2+ current in rat magnocellular neurosecretory cells by activating the NPR-C receptor. Journal of neurophysiology 17 15772242
2002 Dietary salt supplementation selectively downregulates NPR-C receptor expression in kidney independently of ANP. American journal of physiology. Renal physiology 17 11788435
1996 Expression and glucocorticoid regulation of natriuretic peptide clearance receptor (NPR-C) mRNA in rat brain and choroid plexus. Journal of chemical neuroanatomy 16 8951595
2019 Human genotyping and an experimental model reveal NPR-C as a possible contributor to morbidity in coarctation of the aorta. Physiological genomics 14 31002586
2019 Pulmonary Arterial Hypertension Due to NPR-C Mutation: A Novel Paradigm for Normal and Pathologic Remodeling? International journal of molecular sciences 14 31234560
2016 NPR-C gene polymorphism is associated with increased susceptibility to coronary artery disease in Chinese Han population: a multicenter study. Oncotarget 14 27191271
2012 Association of a single nucleotide polymorphism of the NPR3 gene promoter with early onset ischemic stroke in an Italian cohort. European journal of internal medicine 14 22995222
2021 Natriuretic Peptide Clearance Receptor (NPR-C) Pathway as a Novel Therapeutic Target in Obesity-Related Heart Failure With Preserved Ejection Fraction (HFpEF). Frontiers in physiology 13 34093235
2007 C-type natriuretic peptide enhances amylase release through NPR-C receptors in the exocrine pancreas. American journal of physiology. Gastrointestinal and liver physiology 13 17702953
2017 Altered heart rate regulation by the autonomic nervous system in mice lacking natriuretic peptide receptor C (NPR-C). Scientific reports 12 29242602
2005 A new paradigm for hormone recognition and allosteric receptor activation revealed from structural studies of NPR-C. Peptides 12 15911071
2016 Mice with an N-Ethyl-N-Nitrosourea (ENU) Induced Tyr209Asn Mutation in Natriuretic Peptide Receptor 3 (NPR3) Provide a Model for Kyphosis Associated with Activation of the MAPK Signaling Pathway. PloS one 11 27959934
2019 Role of epicardial adipose tissue NPR-C in acute coronary syndrome. Atherosclerosis 10 31102956
1999 Intracellular fragments of the natriuretic peptide receptor-C (NPR-C) attenuate dopamine efflux. Endocrinology 10 10067834
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
2001 Using PAC nested deletions to order contigs and microsatellite markers at the high repetitive sequence containing Npr3 gene locus. Gene 9 11574153
2023 Npr3 regulates neural crest and cranial placode progenitors formation through its dual function as clearance and signaling receptor. eLife 8 37162198
2018 Luteinizing hormone upregulates NPPC and downregulates NPR3 mRNA abundance in bovine granulosa cells through activation of the EGF receptor. Theriogenology 8 29960164
2011 NPR-C protects embryonic stem cells from apoptosis by regulating p53 levels. Stem cells and development 8 21846177
2009 NPR-C is expressed in the cholinergic and dopaminergic amacrine cells in the rat retina. Peptides 8 19878700
2024 CRISPR/Cas9-driven double modification of grapevine MLO6-7 imparts powdery mildew resistance, while editing of NPR3 augments powdery and downy mildew tolerance. The Plant journal : for cell and molecular biology 7 39645650
2022 Circular RNA circPRDX3 mediates neuronal survival apoptosis in ischemic stroke by targeting miR-641 and NPR3. Brain research 7 36208650
2025 The RING-finger ubiquitin E3 ligase RFEL1 targets wheat NPR3 for degradation to confer broad-spectrum resistance against biotrophic fungal pathogens. Molecular plant 6 40671679
2024 Hydrogen peroxide sensitivity connects the activity of COX5A and NPR3 to the regulation of YAP1 expression. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 6 38416461
2024 NPRC promotes hepatic steatosis via USP30-mediated deubiquitination of C/EBPβ. Metabolism: clinical and experimental 6 39433172
2025 Rice-specific miR1850.1 targets NPR3 to regulate cold stress response. Plant communications 5 40156194
2023 Deletion of the Npr3 gene increases severity of acute lung injury in obese mice. Pulmonary circulation 5 37528869
2023 TMT-based quantitative proteomic analysis revealed that FBLN2 and NPR3 are involved in the early osteogenic differentiation of mesenchymal stem cells (MSCs). Aging 5 37543430
2004 Cyclic adenosine monophosphate (cAMP) increases natriuretic peptide receptor C (NPR-C) expression in human aortic smooth muscle cells. Molecular and cellular endocrinology 5 15149737
2025 Podocyte NPRC Deficiency Attenuates Glomerular Fibrosis in Diabetic Mice. Circulation research 4 40557490
2025 FLP-15 functions through the GPCR NPR-3 to regulate local and global search behaviours in Caenorhabditis elegans. bioRxiv : the preprint server for biology 3 40655019
2015 Correlation between natriuretic peptide receptor C (NPR3) gene polymorphisms and hypertension in the Dai people of China. Genetics and molecular research : GMR 3 26345810
2010 Upregulation of ANP and NPR-C mRNA in the kidney and heart of eNOS knockout mice. Peptides 3 20403400
2024 NPR3 is regulated by gonadotropins and modulates bovine cumulus cell expansion. Reproduction (Cambridge, England) 2 39441769
2022 Unraveling NPR-like Family Genes in Fragaria spp. Facilitated to Identify Putative NPR1 and NPR3/4 Orthologues Participating in Strawberry-Colletotrichum fructicola Interaction. Plants (Basel, Switzerland) 2 35736739
2017 Association of NPR3 polymorphism with risk of essential hypertension in a Chinese population. Journal of clinical pharmacy and therapeutics 2 28497617
2016 Data on synthesis and characterization of chitosan nanoparticles for in vivo delivery of siRNA-Npr3: Targeting NPR-C expression in the heart. Data in brief 2 27366782
2026 The Rice Cis-Natural Antisense Transcript NAT1850 of Pri-miR1850 Negatively Regulates Cold Tolerance by Repressing NPR3. Plant biotechnology journal 1 41748166
2026 FLP-15 functions through the GPCR NPR-3 to regulate local and global search behaviours in Caenorhabditis elegans. Communications biology 1 42082704
2025 Deficiency of NPR-C triggers high salt-induced thoracic aortic dissection by impairing mitochondrial homeostasis. Cardiovascular research 1 40377018
2025 IGF2BP3 promotes osteosarcoma malignancy through stabilization of m6A-modified UBE4AmRNA, which involves promotion of NPR3 ubiquitination and degradation. Physiology international 1 40674149
2025 Salicylic acid regulates biosynthesis of floral fragrance (E)-β-farnesene via NPR3-WRKY1 module in chrysanthemum. Molecular horticulture 1 40908482
2025 Inhibition of vascular intimal hyperplasia by the myokine Musclin: the role of NPR3/raptor/mTORC1-mediated glycolysis and phenotypic switching of VSMCs. Acta biochimica et biophysica Sinica 1 41074587
2025 NPR3 promotes colorectal cancer cell proliferation, migration, invasion, and chemotherapy resistance. Biochimica et biophysica acta. General subjects 1 41380984
2024 RNA-Seq data analysis reveals novel nonsense mutations in the NPR3 gene leading to the progression of intellectual disability disorder. Heliyon 1 38765165
2024 Unraveling the role of natriuretic peptide clearance receptor (NPR3) in glomerular diseases. Scientific reports 1 38782980
2024 Skeletal muscle-derived musclin attenuates glycolysis, oxidative stress, and pulmonary hypertension through the NPR3/AKT/mTORC1 pathway. Acta biochimica et biophysica Sinica 1 39632658
2015 Association of NPRA and NPRC gene variants and hypertension in Mongolian population. Genetics and molecular research : GMR 1 26782497
2026 Podocyte specific knockout (KO) of the natriuretic peptide clearance receptor (NPRC) attenuates diabetic kidney disease (DKD). Physiological reports 0 42130223
2025 Targeted inhibition of NPR3/MAPK pathway enhances dental pulp stem cell multipotency: Mechanistic validation based on ligustrazine (TMP). Experimental cell research 0 39984110
2025 Tall Stature and Scoliosis Associated With a Novel Homozygous Loss-of-Function Missense Variant in NPR3. American journal of medical genetics. Part A 0 40171685
2025 Associations of Genetically Predicted NPR3 and NPR2 Perturbation and Preeclampsia Risk: A Two-Sample Mendelian Randomization Analysis. International journal of hypertension 0 40406480
2025 A Pan-Cancer Analysis of Natriuretic Peptide Receptor 3 (NPR3) with Clinical Cohort and in vitro Validation. Journal of inflammation research 0 40740975

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