Affinage

NPR3

Atrial natriuretic peptide receptor 3 · UniProt P17342

Length
541 aa
Mass
59.8 kDa
Annotated
2026-04-29
86 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NPR3 (NPR-C) is a single-transmembrane natriuretic peptide clearance receptor that functions both as a scavenger regulating local natriuretic peptide concentrations and as a signaling receptor coupling through its cytoplasmic domain to Gi1/Gi2 proteins, thereby inhibiting adenylyl cyclase, activating PLC-β3/IP3, and suppressing L-type Ca²⁺ channels in cardiac, neuronal, and smooth muscle cells (PMID:10364194, PMID:14704228, PMID:15772242). The receptor binds natriuretic peptides as a homodimer in 1:2 hormone:receptor stoichiometry with an allosteric conformational switch (PMID:15911071), and its clearance function controls endochondral ossification, as demonstrated by skeletal overgrowth in Npr3-deficient mice and tall stature with aortic dilatation in humans carrying bi-allelic NPR3 loss-of-function mutations (PMID:10468599, PMID:30032985). Beyond hemodynamic and skeletal roles, NPR3 suppresses fibrotic signaling by modulating TGF-βR2 recycling and TGIF1/Smad2/3 pathways in cardiac and renal contexts (PMID:37531438, PMID:40557490), interacts with raptor to inhibit mTORC1 (PMID:39632658), recruits USP30 to stabilize C/EBPβ via deubiquitination in hepatic lipid metabolism (PMID:39433172), and mediates BNP-facilitated histaminergic itch through cross-signaling with NMBR in dorsal horn neurons (PMID:34919054). Bi-allelic loss-of-function mutations in NPR3 cause an autosomal recessive skeletal overgrowth syndrome with tall stature, long digits, extra epiphyses, and aortic root dilatation (PMID:30032985).

Mechanistic history

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

    Establishing that NPR-C is not merely a clearance receptor but an active signaling receptor: the 17-amino acid cytoplasmic peptide (R469–R485) was identified as the minimal Gi-activating sequence that inhibits adenylyl cyclase, activates PLC-β3, and induces smooth muscle contraction, resolving the question of whether NPR-C's short intracellular domain could engage G proteins.

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

    PMID:10364194

    Open questions at the time
    • No structural basis for peptide–Gαi interaction
    • No in vivo validation of the minimal peptide
    • Relative contribution of Gi1 vs. Gi2 not resolved
  2. 1999 High

    Three independent loss-of-function alleles in mouse Npr3 established NPR-C as a physiological regulator of skeletal growth through natriuretic peptide clearance, answering whether the receptor has non-redundant in vivo functions beyond cardiovascular homeostasis.

    Evidence Positional cloning and skeletal analysis of three spontaneous/ENU Npr3 mutant mouse lines showing extended endochondral ossification zones

    PMID:10468599

    Open questions at the time
    • Whether the skeletal phenotype is clearance-dependent or signaling-dependent was unresolved
    • Human genetic validation was missing
  3. 2003 High

    Mutagenesis confirmed the necessity of specific basic residues at both termini of the 17-aa Gi-activating peptide and revealed a C-terminal autoinhibitory domain, defining the structural determinants of NPR-C's signaling capability.

    Evidence Site-directed mutagenesis and deletion analysis of NPR-C intracellular domain with Gi, PLC-β, and adenylyl cyclase readouts

    PMID:12676657

    Open questions at the time
    • No crystal structure of the intracellular domain–Gi complex
    • Autoinhibitory mechanism not characterized at the structural level
  4. 2004 High

    The first physiological consequence of NPR-C Gi signaling was demonstrated in cardiac pacemaking: NPR-C suppresses L-type Ca²⁺ current in sinoatrial node cells, establishing a direct negative chronotropic mechanism.

    Evidence Voltage-clamp electrophysiology on isolated SA node myocytes with selective NPR-C agonist cANF and intracellular dialysis of Gi-activator peptide

    PMID:14704228

    Open questions at the time
    • Contribution to heart rate regulation in intact animals not shown
    • Whether T-type channels are affected in SA node was not tested
  5. 2005 High

    Crystal structures of the NPR-C ectodomain in apo and hormone-bound states revealed a 1:2 ligand:receptor dimer stoichiometry with large-scale allosteric conformational change, providing the first structural framework for natriuretic peptide receptor activation.

    Evidence X-ray crystallography of NPR-C ectodomain

    PMID:15911071

    Open questions at the time
    • Full-length receptor structure including transmembrane and intracellular domains lacking
    • How conformational change propagates to intracellular Gi activation unknown
  6. 2005 High

    Extension of NPR-C's Gi-coupled Ca²⁺ channel suppression to hypothalamic magnocellular neurons demonstrated the receptor operates as a neuronal modulator beyond the cardiovascular system.

    Evidence Whole-cell patch-clamp of magnocellular neurosecretory cells with cANF agonist and Gi-activator peptide dialysis

    PMID:15772242

    Open questions at the time
    • Behavioral or neuroendocrine consequences of NPR-C signaling in hypothalamus not shown
    • Whether NPR-C modulates vasopressin/oxytocin release not addressed
  7. 2007 High

    NPR-C was shown to drive exocrine secretion: CNP stimulates amylase release from pancreatic acini through NPR-C/Gi/PLC-β/IP3 signaling, extending the receptor's effector repertoire to secretory epithelia.

    Evidence Isolated rat pancreatic acini with phosphoinositide hydrolysis, amylase secretion, cAMP/cGMP measurements, and pharmacological inhibitors

    PMID:17702953

    Open questions at the time
    • In vivo relevance to pancreatic function not established
    • Whether NPR-C regulates other exocrine organs not tested
  8. 2016 High

    An ENU missense mutation introducing an aberrant glycosylation site caused NPR3 ER retention, linking loss of plasma membrane NPR3 to increased p38 MAPK signaling in growth plates — demonstrating that MAPK activation mediates the skeletal phenotype.

    Evidence COS-7 expression with localization analysis; immunohistochemistry for p-p38 MAPK; growth plate histomorphometry in mutant mice

    PMID:27959934

    Open questions at the time
    • Whether p38 MAPK activation is direct or secondary to elevated natriuretic peptide signaling not determined
    • Rescue by MAPK inhibition not performed in vivo
  9. 2018 High

    Human bi-allelic NPR3 loss-of-function mutations were shown to cause tall stature, long digits, extra epiphyses, and aortic dilatation, confirming the mouse skeletal phenotype translates to a human Mendelian disease and establishing elevated cGMP/natriuretic peptide signaling as the biochemical hallmark.

    Evidence Family studies with human genetic analysis; in vitro expression showing intracellular retention of mutant receptors; plasma NTproNP/NP ratio and cGMP measurements

    PMID:30032985

    Open questions at the time
    • Aortic phenotype mechanism not resolved — clearance versus signaling contribution unclear
    • Genotype-phenotype correlations across different mutation types not established
  10. 2019 High

    NPR-C knockout mice showed exacerbated angiotensin II-induced atrial fibrillation with increased fibrosis, and NPR-C agonist rescued AF inducibility, answering whether NPR-C protects against atrial arrhythmogenesis through anti-fibrotic and electrophysiological mechanisms.

    Evidence NPR-C KO mice with in vivo electrophysiology, optical mapping, patch clamping, and agonist rescue under Ang II challenge

    PMID:30636477

    Open questions at the time
    • Whether the anti-AF effect is Gi-signaling-dependent or clearance-dependent not dissected
    • Human relevance of NPR-C in atrial fibrillation not established
  11. 2021 High

    In the spinal dorsal horn, NPR-C was found to mediate BNP-facilitated histaminergic itch through cross-signaling with NMBR, revealing an unexpected receptor crosstalk mechanism in somatosensory circuits.

    Evidence Behavioral scratching assays in Npr3 KO mice; Ca²⁺ imaging in NMBR/NPRC co-expressing HEK293 cells and dorsal horn neurons

    PMID:34919054

    Open questions at the time
    • Molecular mechanism of NPRC-NMBR cross-signaling not identified
    • Whether Gi coupling mediates the itch response not tested
  12. 2022 High

    miR-146a was identified as a direct post-transcriptional regulator of NPR3 in adipocytes, and CRISPR knockout of NPR3 enhanced insulin-stimulated glucose uptake and lipogenesis, establishing NPR3 as a metabolic gatekeeper in adipose tissue.

    Evidence miR-146a KO mice on HFD; CRISPR/Cas9 NPR3 KO in SGBS adipocytes; insulin-stimulated glucose uptake and de novo lipogenesis assays

    PMID:33206203

    Open questions at the time
    • How NPR3 suppresses insulin signaling mechanistically is undefined
    • Whether adipocyte NPR3 signals via Gi or acts solely as a clearance receptor not resolved
  13. 2023 High

    NPR-C deletion attenuated cardiac and renal fibrosis by upregulating TGIF1 (via cAMP/PKA and cGMP/PKG) to inhibit Smad2/3 phosphorylation, and separately by redirecting TGF-βR2 from recycling to degradation — revealing two distinct anti-fibrotic mechanisms downstream of NPR-C loss.

    Evidence NPRC KO diabetic mice; podocyte-specific KO; RNA-seq; TGF-βR2 recycling assays; Western blot for Smad2/3 and TGIF1

    PMID:37531438 PMID:40557490

    Open questions at the time
    • Whether NPR-C physically interacts with TGF-βR2 directly or via adaptors is unknown
    • TGIF1 regulation in non-diabetic fibrosis contexts not tested
  14. 2023 High

    In Xenopus, Npr3 was shown to play a dual clearance/signaling role in segregating neural crest and cranial placode progenitors by modulating local cGMP (via Npr1) and cAMP levels, establishing a developmental patterning function for the receptor.

    Evidence Morpholino knockdown, pharmacological inhibitors, and rescue assays in Xenopus embryos with second messenger quantification

    PMID:37162198

    Open questions at the time
    • Whether this dual mechanism operates in mammalian neural crest development not established
    • Spatiotemporal dynamics of natriuretic peptide gradients not directly measured
  15. 2024 High

    NPR-C was found to recruit the deubiquitinase USP30 via its ANPR domain to stabilize C/EBPβ by removing K48-linked polyubiquitin at K149, linking NPR-C to transcription factor stabilization and hepatic lipid metabolism reprogramming.

    Evidence Proteomic and ubiquitination analyses; co-IP; in vitro ubiquitination assay with site-specific ubiquitin mapping

    PMID:39433172

    Open questions at the time
    • Whether USP30 recruitment is ligand-dependent not tested
    • Structural basis of ANPR-USP30 interaction unknown
  16. 2024 Medium

    NPR-C was shown to interact with raptor and suppress mTORC1 activity in a musclin-dependent manner in pulmonary arterial SMCs, identifying a new non-Gi signaling axis for NPR-C.

    Evidence Co-IP for NPR3-raptor; siRNA knockdown of NPR3; mTORC1 activity, glycolysis, proliferation, and migration assays; AAV6-musclin in PH mouse model

    PMID:39632658

    Open questions at the time
    • Direct binding interface between NPR3 and raptor not mapped
    • Whether endogenous natriuretic peptides also trigger raptor interaction not tested
    • Single lab finding awaiting independent confirmation
  17. 2025 High

    VSMC-specific NPR-C deletion triggered thoracic aortic dissection via ERK1/2 activation, decreased PPARγ/HADHB, and impaired mitochondrial fatty acid oxidation, revealing a cell-type-specific vascular protective mechanism.

    Evidence VSMC-specific and EC-specific NPR-C KO mice; RNA-seq; pharmacological rescue with C-ANP4-23 and spermidine

    PMID:40377018

    Open questions at the time
    • How NPR-C suppresses ERK1/2 in VSMCs — via Gi or clearance — not resolved
    • Whether this mechanism applies to abdominal aortic pathology unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: how NPR-C's conformational change propagates from the ectodomain through the single transmembrane helix to the intracellular Gi-activating domain; the structural basis of the NPR-C–raptor and NPR-C–TGF-βR2 interactions; and whether the receptor's diverse tissue-specific functions (cardiac, skeletal, metabolic, neural) are driven primarily by clearance, Gi signaling, or non-canonical protein–protein interactions.
  • No full-length NPR-C structure available
  • Relative contributions of clearance vs. Gi signaling vs. protein interactions not systematically dissected in any tissue
  • No integrative model reconciling the numerous downstream effector pathways

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0098772 molecular function regulator activity 5 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-162582 Signal Transduction 10 R-HSA-1643685 Disease 6 R-HSA-1266738 Developmental Biology 4 R-HSA-1430728 Metabolism 2
Partners
CEBPBGNAI1GNAI2NMBRPLCB3RPTORTGFBR2USP30

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 The 37-amino acid intracellular domain of NPR-C activates selectively Gi1 and Gi2; a 17-amino acid peptide (Arg469-Arg485) in the middle region of the cytoplasmic domain, possessing N-terminal arginine residues and a C-terminal B-B-X-X-B motif, was identified as the G protein-activating sequence that binds Gi1/Gi2, activates PLC-beta3 via betagamma subunits, inhibits adenylyl cyclase, and induces smooth muscle contraction. Synthetic peptide fragments of NPR-C cytoplasmic domain used in biochemical assays (Gi binding, adenylyl cyclase inhibition, PLC activation, smooth muscle contraction) The Journal of biological chemistry High 10364194
2003 Site-directed mutagenesis 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 activation of Gi1, Gi2, PLC-beta, and inhibition of adenylyl cyclase; substitution of N-terminal arginines (R469R470) or C-terminal basic residues (H481, R482, R485) abolished all G protein and effector activities; deletion of the 11 C-terminal residues suggested an autoinhibitory function. Site-directed mutagenesis and deletion analysis of NPR-C intracellular domain expressed in cells; functional assays for Gi activation, PLC-beta activity, adenylyl cyclase inhibition American journal of physiology. Cell physiology High 12676657
1999 Three allelic loss-of-function mutations in the mouse Npr3 gene (lgj, stri, lgj2J) cause skeletal overgrowth with extended endochondral ossification proliferation zones, establishing NPR-C as a natriuretic peptide clearance receptor with an in vivo role in bone growth via natriuretic peptide clearance. Genetic mapping and sequencing of spontaneous/ENU mutant mice; skeletal preparation analysis; positional cloning Proceedings of the National Academy of Sciences of the United States of America High 10468599
2005 Crystal structure of the NPR-C extracellular domain in quiescent and hormone-bound forms reveals that hormone (natriuretic peptide) intercalates within the interface of a receptor homodimer in 1:2 stoichiometry, inducing a large-scale conformational change in the membrane-proximal regions; this allosteric activation mechanism is proposed to be conserved across the NPR family. X-ray crystallography of NPR-C ectodomain in apo and ligand-bound forms Peptides High 15911071
2004 CNP and the selective NPR-C agonist cANF significantly inhibit L-type Ca2+ current (ICa(L)) in mouse sinoatrial node myocytes via NPR-C-coupled Gi protein signaling; a 17-amino acid Gi-activator peptide from NPR-C's intracellular domain dialyzed into SA node cells reproduced the decrease in ICa(L), providing first evidence of NPR-C-mediated negative chronotropy. Voltage-clamp electrophysiology on isolated SA node myocytes; Langendorff perfused hearts; intracellular dialysis of NPR-C Gi-activator peptide American journal of physiology. Heart and circulatory physiology High 14704228
2005 CNP and cANF inhibit L-type Ca2+ current (~50%) and reduce excitability in magnocellular neurosecretory cells (MNCs) via NPR-C receptor coupled to Gi protein; T-type Ca2+ channels are unaffected; a Gi-activator peptide from NPR-C's intracellular domain mimicked the effect, providing first electrophysiological evidence of functional NPR-C in the mammalian hypothalamus. Whole-cell patch-clamp recordings from acutely isolated MNCs and brain slice; intracellular dialysis of NPR-C Gi-activator peptide Journal of neurophysiology High 15772242
1999 A pentadecapeptide segment of the NPR-C cytoplasmic domain mimicked natriuretic peptides in suppressing calcium-evoked dopamine efflux (~40%) in permeabilized PC12 cells; an antibody against this peptide abolished the neuromodulatory effect of CNP, implicating the membrane-proximal cytoplasmic region of NPR-C in transducing neuromodulatory effects. Digitonin-permeabilized PC12 cells with peptide fragments and neutralizing antibody; dopamine efflux assay Endocrinology Medium 10067834
2001 Tyrosine kinase receptor activation by FGF-1, FGF-2, and PDGF-BB (but not hypoxia, ANP, ANG II, ET-1, or cGMP) dose- and time-dependently reduces NPR-C mRNA in pulmonary arterial smooth muscle cells; this downregulation is blocked by an FGF receptor tyrosine kinase inhibitor and MEK/ERK inhibitors, placing NPR-C expression downstream of tyrosine kinase/ERK signaling. Northern blot of NPR-C mRNA in growth factor-treated PASMCs; pharmacological inhibition of receptor tyrosine kinase and MAPK/ERK pathway American journal of physiology. Lung cellular and molecular physiology Medium 11404258
2003 ANF stimulates exocrine pancreatic secretion via NPR-C receptors coupled to the phosphoinositide (PLC) pathway; the NPR-C-selective agonist cANP(4-23) mimicked ANF's effect; in isolated pancreatic acini, ANF dose-dependently enhanced phosphoinositide hydrolysis blocked by PLC inhibitor U-73122, without modifying cAMP. In vivo pancreatic secretion assay in anesthetized rats; isolated pancreatic acini; phosphoinositide hydrolysis assay; pharmacological inhibition with U-73122 and pertussis toxin American journal of physiology. Gastrointestinal and liver physiology High 12829435
2006 NPR-C activates NOS (leading to NO production) in atria via Gi protein coupling; in kidney and vasculature, NOS activation by ANP also involves NPR-A/B; NPR-C-mediated NOS activation is calcium-dependent, blocked by nifedipine and calmodulin antagonist, and pertussis toxin-sensitive in atria. NOS activity assay using L-[U14C]-arginine in kidney, aorta, and heart tissue from rats; pharmacological antagonism with pertussis toxin, nifedipine, calmidazolium; NPR-C-selective ligand cANP(4-23) Regulatory peptides Medium 16712979
2007 CNP stimulates amylase release from pancreatic acini through NPR-C receptors coupled to PLC pathway (blocked by U-73122 and IP3 receptor antagonist 2-APB) and partially via PKC; pertussis toxin sensitivity confirms Gi coupling; higher CNP concentrations activate NPR-A/B increasing cGMP and reducing cAMP to attenuate secretion. Isolated rat pancreatic acini; amylase secretion assay; phosphoinositide hydrolysis; cAMP/cGMP measurements; pharmacological inhibition with pertussis toxin, U-73122, 2-APB, GF-109203X American journal of physiology. Gastrointestinal and liver physiology High 17702953
2016 An ENU-induced Tyr209Asn missense mutation in NPR3 introduces an aberrant N-linked glycosylation site, causing endoplasmic reticulum retention and absence of NPR3 from the plasma membrane; loss of membrane NPR3 results in increased p38 MAPK phosphorylation in growth plates, delayed endochondral ossification, expanded hypertrophic zones, and kyphosis. COS-7 cell expression of wild-type and mutant NPR3 with Western blot and localization analysis; immunohistochemistry for p38 MAPK phosphorylation; histomorphometry of growth plates; ENU mutant mouse model PloS one High 27959934
2018 Bi-allelic loss-of-function mutations in NPR3 cause tall stature, long digits, extra epiphyses, and aortic dilatation in humans; missense mutations (p.Ser148Pro and p.Asp363Val) result in intracellular retention and absent plasma membrane localization of NPR-C; the nonsense mutation causes NMD; biochemically, reduced NTproNP/NP ratio and high cGMP indicate reduced natriuretic peptide clearance and increased NPR-A/B signaling. Human genetic analysis; in vitro expression of mutant receptors with subcellular localization studies; biochemical plasma peptide and cGMP measurement American journal of human genetics High 30032985
2015 MicroRNA-100 (miR-100) directly regulates NPR3 expression post-transcriptionally; antagomir-based silencing of miR-100 enhanced NPR3 expression in cardiac cells; miR-100 is upregulated in hypoxic conditions and after myocardial infarction, correlating with NPR3 downregulation. MicroRNA microarray; qRT-PCR; antagomir-based silencing in HCMa cells; ELISA; rat MI model Journal of molecular and cellular cardiology Medium 25736855
2016 NPR3 knockdown in H9C2 cardiomyocytes activates caspase-3, 8, and 9, increases CREB activity, upregulates cytoplasmic BRCA1, and increases TNF-α expression, demonstrating that NPR3 protects cardiomyocytes from apoptosis by suppressing both intrinsic and extrinsic apoptotic pathways through inhibition of cytosolic BRCA1 and TNF-α. Stable shRNA knockdown of NPR3 in H9C2 cells; caspase activity assays; Western blot for BRCA1 and CREB; TNF-α expression analysis Cell cycle (Georgetown, Tex.) Medium 27494651
2011 NPR-C is required for survival of murine embryonic stem cells; NPR-C knockdown by siRNA causes apoptotic cell death with induction of p53 protein; chemical inhibition of p53 reduces apoptosis in NPR-C-deficient cells; selective NPR-C agonist cANF(4-23) protects ES cells from oxidative stress-induced apoptosis by blocking p53 activation. siRNA knockdown of NPR-C in murine ES cells; flow cytometry for apoptosis; Western blot for p53; pharmacological p53 inhibition; agonist treatment with cANF(4-23) Stem cells and development Medium 21846177
2019 NPR-C knockout mice show exacerbated Ang II-induced atrial fibrillation susceptibility, greater action potential duration prolongation, reduced Vmax, and substantially increased atrial fibrosis compared to wild-type; NPR-C agonist cANF dose-dependently reduced AF inducibility; NPR-C modulates atrial electrophysiology and structural remodeling in Ang II-mediated AF via effects on TGFβ and TIMP1 expression. In vivo electrophysiology in NPR-C knockout and wild-type mice; optical mapping; patch clamping; molecular biology; Ang II infusion model; agonist cotreament Circulation. Arrhythmia and electrophysiology High 30636477
2016 NPR-C (Npr3) is expressed by cells associated with dorsal roots but not in DRG neurons at early developmental stages; Npr3-deficient mice show that a small population of sensory axons (13%) fail to form T-like branches and generate only rostral/caudal turns, indicating NPR-C has a minor role in the scavenging of CNP to regulate sensory axon bifurcation. In situ hybridization; immunohistology; tracking of DRG sensory axons in Npr3-deficient mice; cGMP sensor imaging; RT-PCR The European journal of neuroscience Medium 27740716
2021 NPRC (encoded by Npr3) is expressed in dorsal horn neurons overlapping with NMBR; NPRC is required for histamine-evoked itch but not chloroquine-evoked itch; BNP facilitates NMB-induced scratching via NPRC-NMBR cross-signaling; BNP evokes Ca2+ responses in cells co-expressing NMBR and NPRC, revealing a novel receptor crosstalk mechanism for itch transmission. Behavioral scratching assays in Npr3 knockout mice; calcium imaging in NMBR/NPRC HEK293 cells and dorsal horn neurons; in situ hybridization for co-expression eLife High 34919054
2023 NPRC deletion in cardiomyocytes and cardiac fibroblasts decreases collagen synthesis and fibroblast proliferation; mechanistically, NPRC deletion upregulates TGIF1 via cAMP/PKA and cGMP/PKG activation, and TGIF1 inhibits Smad2/3 phosphorylation, thereby attenuating TGF-β1/Smad fibrotic signaling in diabetic cardiomyopathy. NPRC-/- diabetic mouse model; cardiac fibroblast and cardiomyocyte knockdown; RNA sequencing; Western blot; echocardiography Science advances High 37531438
2023 NPRC deletion reduces atherosclerotic lesion size and instability in ApoE-/- mice; endothelial NPRC knockdown inhibits ROS production, NF-κB-driven inflammation, and apoptosis while increasing eNOS; mechanistically, NPRC deletion activates cAMP/PKA pathway, upregulating AKT1 and downregulating NF-κB signaling. ApoE-/- NPRC-/- double KO mice; endothelial cell-specific NPRC KO and overexpression; in vitro NPRC knockdown in HAECs; Western blot; ROS assay; macrophage co-culture experiments Signal transduction and targeted therapy High 37553374
2023 Npr3 (NPR-C) plays a pivotal dual role in Xenopus neural crest (NC) and cranial placode (CP) progenitor formation: as a clearance receptor it regulates local natriuretic peptide concentrations for optimal cGMP production through Npr1 activation, and as a signaling receptor it controls cAMP levels via adenylyl cyclase inhibition; the intracellular modulation of cGMP and cAMP participates in segregation of NC and CP cell populations. Morpholino knockdown, pharmacological inhibitors, and rescue assays in Xenopus; genetic epistasis with Npr1, Nppa, Nppc; second messenger measurement eLife High 37162198
2022 miR-146a directly targets NPR3 in adipocytes; CRISPR/Cas9-mediated knockout of NPR3 increases insulin-stimulated glucose uptake and enhances de novo lipogenesis in SGBS adipocytes; miR-146a knockout mice on high-fat diet show increased body weight, fat mass, insulin resistance, and glucose intolerance, partly mediated through NPR3. miR-146a-/- mice on HFD; adipocyte transfection with miR-146a inhibitor/mimic; CRISPR/Cas9 NPR3 KO in adipocytes; insulin-stimulated glucose uptake assay; de novo lipogenesis assay Cellular and molecular life sciences : CMLS High 33206203
2024 NPRC recruits deubiquitinase USP30 to stabilize C/EBPβ protein: the ANPR region of NPRC binds USP30, which inhibits K149-specific K48-linked polyubiquitination of C/EBPβ via its DBD interaction, preventing C/EBPβ proteasomal degradation and driving lipid metabolism reprogramming in MAFLD. Proteomic and ubiquitination analyses; co-IP; Western blot; in vitro ubiquitination assay; site-specific ubiquitination identification Metabolism: clinical and experimental High 39433172
2024 NPRC deficiency in podocytes decreases recycling and increases degradation of TGF-βR2, thereby suppressing TGF-β1/Smad2/3 signaling and collagen synthesis; podocyte-specific NPRC KO mice show reduced glomerular fibrosis and improved renal function in diabetic kidney disease. Podocyte-specific NPRC knockout mice; mass spectrometry; Western blot; ELISA; histological staining; TGF-βR2 recycling assay Circulation research High 40557490
2025 NPR-C deficiency in vascular smooth muscle cells (but not endothelial cells) triggers thoracic aortic dissection under angiotensin II plus high salt; mechanistically, NPR-C loss activates ERK1/2 pathway, decreasing PPARγ activity and HADHB expression, impairing mitochondrial fatty acid oxidation and homeostasis. VSMC-specific and EC-specific NPR-C KO mice; RNA sequencing; Western blot; pharmacological rescue with C-ANP4-23 and spermidine Cardiovascular research High 40377018
2024 Musclin binds NPR3 and enhances NPR3-raptor interaction in pulmonary arterial smooth muscle cells, inhibiting mTORC1 activity; NPR3 silencing reverses musclin-mediated suppression of AKT phosphorylation, mTORC1 activity, glycolysis, oxidative stress, proliferation, and migration in hypoxia-challenged PASMCs. Co-IP for NPR3-raptor interaction; NPR3 siRNA knockdown; mTORC1 activity assay; ECAR for glycolysis; proliferation and migration assays; AAV6-mediated musclin overexpression in MCT-PH mouse model Acta biochimica et biophysica Sinica Medium 39632658
2021 NPR3 knockdown in H9C2 cardiomyocytes, osteosarcoma cells, and dental pulp stem cells activates the PI3K/AKT pathway and ERK1/2 phosphorylation, respectively, indicating that NPR3 functions as a suppressor of these mitogenic signaling pathways. shRNA/siRNA knockdown of NPR3; Western blot for PI3K/AKT and ERK1/2 phosphorylation; cell viability and apoptosis assays; PI3K inhibitor rescue experiments Cellular signalling Medium 34229087
2022 UBP12 and UBP13 deubiquitinases interact with NPR3 in the nucleus in an SA-dependent manner and remove ubiquitin from polyubiquitinated NPR3 to protect it from 26S proteasomal degradation; in the absence of pathogen challenge, NPR3/NPR4 are unstable and degraded by the proteasome; SA stabilizes NPR3/NPR4; UBP12/UBP13-mediated NPR3 stability suppresses plant immunity. Co-IP for UBP12/UBP13-NPR3 interaction in planta; genetic epistasis in Arabidopsis; ubiquitination assay; proteasome inhibitor treatment; SA treatment Molecular plant High 36415131
2012 Arabidopsis NPR3 and NPR4 are SA receptors that bind SA with different affinities and function as adaptors of Cullin 3 ubiquitin E3 ligase to mediate NPR1 degradation in an SA-regulated manner; the npr3 npr4 double mutant accumulates higher NPR1 levels and is insensitive to SAR induction; NPR3 also interacts with NPR1 and TGA2 in vivo. SA binding assays; Cullin 3 E3 ligase adaptor biochemistry; genetic analysis of npr3 npr4 double mutants; bimolecular fluorescence complementation for NPR3-NPR1-TGA2 interaction Nature High 22699612
2018 Arabidopsis NPR3/NPR4 function as transcriptional co-repressors (not primarily as E3 ligase adaptors for NPR1 degradation); SA inhibits NPR3/NPR4 co-repressor activities to promote expression of downstream immune regulators; a gain-of-function npr4-4D allele unable to bind SA constitutively represses SA-induced immune responses; NPR3/NPR4 and NPR1 function independently in parallel pathways. Genetic analysis of gain-of-function alleles; transcriptional assays; SA-binding assays; double mutant analysis in Arabidopsis Cell High 29656896
2025 Musclin-NPR3 interaction in VSMCs induces NPR3-raptor binding, inhibiting mTORC1 activity and suppressing PDGF-BB-induced VSMC phenotypic switching, glycolysis, proliferation, and migration; NPR3 silencing abrogates all musclin-mediated effects, linking NPR3 to mTORC1/raptor-mediated vascular smooth muscle cell regulation. Co-IP for NPR3-raptor interaction; NPR3 siRNA; ECAR glycolysis assay; ki-67 and transwell assays; AAV6 musclin overexpression in vascular injury mouse model Acta biochimica et biophysica Sinica Medium 41074587

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 657 22699612
2018 Opposite Roles of Salicylic Acid Receptors NPR1 and NPR3/NPR4 in Transcriptional Regulation of Plant Immunity. Cell 518 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 129 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 78 21900499
2023 NPRC deletion attenuates cardiac fibrosis in diabetic mice by activating PKA/PKG and inhibiting TGF-β1/Smad pathways. Science advances 69 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
2010 NPR-C: a component of the natriuretic peptide family with implications in human diseases. Journal of molecular medicine (Berlin, Germany) 56 20563546
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 55 30636477
2023 NPRC deletion mitigated atherosclerosis by inhibiting oxidative stress, inflammation and apoptosis in ApoE knockout mice. Signal transduction and targeted therapy 49 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
2015 Integrating data on the Arabidopsis NPR1/NPR3/NPR4 salicylic acid receptors; a differentiating argument. Frontiers in plant science 45 25914712
2012 The salicylic acid receptor NPR3 is a negative regulator of the transcriptional defense response during early flower development in Arabidopsis. Molecular plant 37 22986789
2016 Salicylic Acid Regulates Pollen Tip Growth through an NPR3/NPR4-Independent Pathway. Molecular plant 35 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 34 15959462
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
2020 miR-146a regulates insulin sensitivity via NPR3. Cellular and molecular life sciences : CMLS 30 33206203
2015 Natriuretic peptide receptor 3 (NPR3) is regulated by microRNA-100. Journal of molecular and cellular cardiology 30 25736855
2022 UBP12/UBP13-mediated deubiquitination of salicylic acid receptor NPR3 suppresses plant immunity. Molecular plant 29 36415131
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
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 28 30032985
2006 Role of NPR-C natriuretic receptor in nitric oxide system activation induced by atrial natriuretic peptide. Regulatory peptides 27 16712979
2011 Impact of natriuretic peptide clearance receptor (NPR3) gene variants on blood pressure in type 2 diabetes. Diabetes care 23 21464461
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 22 35841070
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 19 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
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
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 12 34093235
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
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 5 39433172
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 The RING-finger ubiquitin E3 ligase RFEL1 targets wheat NPR3 for degradation to confer broad-spectrum resistance against biotrophic fungal pathogens. Molecular plant 4 40671679
2025 Rice-specific miR1850.1 targets NPR3 to regulate cold stress response. Plant communications 3 40156194
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
2025 Podocyte NPRC Deficiency Attenuates Glomerular Fibrosis in Diabetic Mice. Circulation research 2 40557490
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
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
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 The Rice Cis-Natural Antisense Transcript NAT1850 of Pri-miR1850 Negatively Regulates Cold Tolerance by Repressing NPR3. Plant biotechnology journal 0 41748166
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
2025 Salicylic acid regulates biosynthesis of floral fragrance (E)-β-farnesene via NPR3-WRKY1 module in chrysanthemum. Molecular horticulture 0 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 0 41074587
2025 NPR3 promotes colorectal cancer cell proliferation, migration, invasion, and chemotherapy resistance. Biochimica et biophysica acta. General subjects 0 41380984
2024 RNA-Seq data analysis reveals novel nonsense mutations in the NPR3 gene leading to the progression of intellectual disability disorder. Heliyon 0 38765165