Details for: NPR3

Gene ID: 4883

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: NPR3

Ensembl ID: ENSG00000113389

Description: natriuretic peptide receptor 3

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • enteric smooth muscle cell CL0002504
    CSI 8.81
    rCSI 12.57%
    PRS 87.93
  • parietal epithelial cell CL1000452
    CSI 7.93
    rCSI 21.18%
    PRS 80.99
  • myofibroblast cell CL0000186
    CSI 7
    rCSI 9.69%
    PRS 84.17
  • hematopoietic stem cell CL0000037
    CSI 5.43
    rCSI 3.61%
    PRS 89.38
  • stromal cell CL0000499
    CSI 5.2
    rCSI 14.64%
    PRS 83.21
  • interstitial cell of Cajal CL0002088
    CSI 4.5
    rCSI 5.73%
    PRS 91.55
  • kidney loop of Henle thin descending limb epithelial cell CL1001111
    CSI 4.02
    rCSI 5.7%
    PRS 84.87
  • VIP GABAergic cortical interneuron CL4023016
    CSI 3.78
    rCSI 4.52%
    PRS 72.74
  • neural crest cell CL0011012
    CSI 3.61
    rCSI 2.86%
    PRS 79.11
  • kidney connecting tubule epithelial cell CL1000768
    CSI 3.49
    rCSI 8.86%
    PRS 80.02
  • endocardial cell CL0002350
    CSI 3.47
    rCSI 16.62%
    PRS 83.59
  • regular ventricular cardiac myocyte CL0002131
    CSI 3.43
    rCSI 21.42%
    PRS 80.63
  • megakaryocyte-erythroid progenitor cell CL0000050
    CSI 3.37
    rCSI 3.05%
    PRS 86.29
  • pulmonary artery endothelial cell CL1001568
    CSI 3.07
    rCSI 4.17%
    PRS 92.77
  • basal cell of epidermis CL0002187
    CSI 3.04
    rCSI 5.39%
    PRS 57.79
  • epithelial cell of proximal tubule CL0002306
    CSI 2.88
    rCSI 7.04%
    PRS 80.4
  • early lymphoid progenitor CL0000936
    CSI 2.77
    rCSI 2.43%
    PRS 91.27
  • lung endothelial cell CL1001567
    CSI 2.76
    rCSI 6.44%
    PRS 94.32
  • hematopoietic precursor cell CL0008001
    CSI 2.66
    rCSI 2.74%
    PRS 94.48
  • mesodermal cell CL0000222
    CSI 2.37
    rCSI 2.84%
    PRS 86.17
  • hematopoietic multipotent progenitor cell CL0000837
    CSI 2.31
    rCSI 5.56%
    PRS 95.59
  • hepatic stellate cell CL0000632
    CSI 2.29
    rCSI 8.56%
    PRS 81.8
  • common myeloid progenitor CL0000049
    CSI 2.23
    rCSI 1.8%
    PRS 89.27
  • epicardial adipocyte CL1000309
    CSI 2.2
    rCSI 7.15%
    PRS 84.68
  • adipocyte CL0000136
    CSI 2.09
    rCSI 2.69%
    PRS 78.41
  • mesenchymal cell CL0008019
    CSI 1.86
    rCSI 4.74%
    PRS 81.97
  • common lymphoid progenitor CL0000051
    CSI 1.86
    rCSI 2.49%
    PRS 96.7
  • vascular associated smooth muscle cell CL0000359
    CSI 1.7
    rCSI 5.5%
    PRS 85.6
  • renal interstitial pericyte CL1001318
    CSI 1.56
    rCSI 4.31%
    PRS 83.98
  • cardiac muscle cell CL0000746
    CSI 1.37
    rCSI 1.97%
    PRS 78.91
  • podocyte CL0000653
    CSI 1.21
    rCSI 5.36%
    PRS 88.15
  • endothelial cell of uterus CL0009095
    CSI 1.17
    rCSI 8.53%
    PRS 92.64
  • CD8-positive, alpha-beta memory T cell, CD45RO-positive CL0001203
    CSI 1.16
    rCSI 1.4%
    PRS 67.95
  • retinal ganglion cell CL0000740
    CSI 1.05
    rCSI 2.31%
    PRS 75.54
  • erythroid progenitor cell CL0000038
    CSI 0.91
    rCSI 5.2%
    PRS 90.45
  • flat midget bipolar cell CL4033033
    CSI 0.76
    rCSI 5.42%
    PRS 77.76
  • GABAergic amacrine cell CL4030027
    CSI 0.7
    rCSI 2.39%
    PRS 74.25
  • myeloid lineage restricted progenitor cell CL0000839
    CSI 0.7
    rCSI 3.6%
    PRS 96.47
  • megakaryocyte progenitor cell CL0000553
    CSI 0.53
    rCSI 9.63%
    PRS 97.16
  • vein endothelial cell of respiratory system CL4033008
    CSI 0.39
    rCSI 2.68%
    PRS 91.44
  • ON midget ganglion cell CL4033046
    CSI 0.37
    rCSI 7.63%
    PRS 78.01
  • OFF midget ganglion cell CL4033047
    CSI 0.33
    rCSI 6.7%
    PRS 78.87

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [NPR3](/details-gene/4883), or natriuretic peptide receptor 3, encodes a key regulator of the natriuretic peptide system. Primarily known as a "clearance receptor," it binds and internalizes natriuretic peptides, thereby controlling their local and systemic concentrations. Functionally, it is implicated in a wide range of physiological processes, including the regulation of blood pressure, skeletal system development, and angiogenesis. **Overall**, expression data reveals its highest significance in structural and contractile cells, such as `enteric smooth muscle cell` ([CL0002504](/details-cell/CL0002504)) and `myofibroblast cell` ([CL0000186](/details-cell/CL0000186)), as well as in specialized epithelial cells like the `parietal epithelial cell` ([CL1000452](/details-cell/CL1000452)) of the kidney. Its widespread yet specific expression pattern underscores its importance in maintaining cardiovascular, renal, and musculoskeletal homeostasis. Loss-of-function mutations have been associated with enhanced growth and connective tissue abnormalities ([Link](https://doi.org/10.1016/j.ajhg.2018.06.007)), highlighting its clinical relevance. ## Cellular Roles and Expression Landscape The expression profile of [NPR3](/details-gene/4883) points to a fundamental role in mesenchymal- and epithelial-derived tissues responsible for filtration, contraction, and structural support. **Overall**, its most significant expression is observed in `enteric smooth muscle cell` ([CL0002504](/details-cell/CL0002504)) (CSI: 8.81), suggesting a role in regulating gastrointestinal motility through natriuretic peptide clearance. High significance in `parietal epithelial cell` ([CL1000452](/details-cell/CL1000452)) (CSI: 7.93) and other kidney cells, such as `kidney loop of Henle thin descending limb epithelial cell` ([CL1001111](/details-cell/CL1001111)), is consistent with its established function in renal physiology and fluid balance. Furthermore, [NPR3](/details-gene/4883) is a prominent marker in cells critical for tissue structure and repair, including `myofibroblast cell` ([CL0000186](/details-cell/CL0000186)) (CSI: 7.00) and `stromal cell` ([CL0000499](/details-cell/CL0000499)) (CSI: 5.20). Its expression extends to the cardiovascular system, with notable significance in `endocardial cell` ([CL0002350](/details-cell/CL0002350)) and `regular ventricular cardiac myocyte` ([CL0002131](/details-cell/CL0002131)), and to progenitor populations like `hematopoietic stem cell` ([CL0000037](/details-cell/CL0000037)) and `megakaryocyte-erythroid progenitor cell` ([CL0000050](/details-cell/CL0000050)). This broad but distinct expression pattern suggests that [NPR3](/details-gene/4883) is a pleiotropic regulator, fine-tuning peptide signaling across diverse physiological systems. ## Pathways and Molecular Function [NPR3](/details-gene/4883) functions as a homodimeric transmembrane receptor located on the `plasma membrane` ([GO:0005886](/details-gene/GO:0005886)). Its primary molecular function is `natriuretic peptide receptor activity` ([GO:0016941](/details-gene/GO:0016941)) and `peptide hormone binding` ([GO:0017046](/details-gene/GO:0017046)). Unlike NPR1 and NPR2, it lacks an intracellular guanylyl cyclase domain and was historically thought to function solely in ligand clearance. However, evidence suggests it can also participate in G protein-coupled receptor signaling ([GO:0007186](/details-gene/GO:0007186)), thereby inhibiting adenylyl cyclase. The biological processes associated with [NPR3](/details-gene/4883) are directly linked to its role in modulating natriuretic peptide levels. It is a critical component of the `regulation of blood pressure` ([GO:0008217](/details-gene/GO:0008217)) and is involved in `angiogenesis` ([GO:0001525](/details-gene/GO:0001525]) and `blood vessel remodeling` ([GO:0001974](/details-gene/GO:0001974)). Its involvement in `skeletal system development` ([GO:0001501](/details-gene/GO:0001501]) is supported by clinical findings where biallelic loss-of-function mutations lead to skeletal overgrowth phenotypes ([Link](https://doi.org/10.1016/j.ajhg.2018.06.007)). This indicates that beyond its cardiovascular roles, [NPR3](/details-gene/4883) is a key negative regulator of endochondral ossification. ## Research Directions The diverse expression pattern and dual functionality (clearance and signaling) of [NPR3](/details-gene/4883) present several avenues for future investigation. **Proposed Hypotheses:** 1. Given its high expression in `myofibroblast cell` ([CL0000186](/details-cell/CL0000186)) and `stromal cell` ([CL0000499](/details-cell/CL0000499)), and the known anti-fibrotic properties of natriuretic peptides, [NPR3](/details-gene/4883) may act as a pro-fibrotic gatekeeper in tissues like the heart and kidney by clearing locally produced anti-fibrotic peptides. Its upregulation during tissue injury could therefore exacerbate fibrotic remodeling. 2. The significant expression of [NPR3](/details-gene/4883) in `enteric smooth muscle cell` ([CL0002504](/details-cell/CL0002504)) and `interstitial cell of Cajal` ([CL0002088](/details-cell/CL0002088)) suggests a previously underappreciated role in regulating gastrointestinal motility. By controlling the local bioavailability of natriuretic peptides or other unidentified peptide ligands, it may modulate gut contractility, and its dysregulation could contribute to motility disorders. **Experimental Approach:** To test the hypothesis that [NPR3](/details-gene/4883) is a pro-fibrotic regulator (Hypothesis 1), a conditional knockout mouse model could be employed. Specifically, deleting [NPR3](/details-gene/4883) in a myofibroblast-specific manner (e.g., using a Periostin-Cre driver) followed by a cardiac injury model like transverse aortic constriction (TAC) would be informative. The primary endpoints would be to assess cardiac fibrosis via Masson's trichrome staining and collagen quantification, measure expression of fibrotic genes (e.g., *Col1a1*, *Acta2*) using RNA-seq or qPCR, and evaluate cardiac function by echocardiography. A reduction in fibrosis in the knockout mice compared to controls would validate [NPR3](/details-gene/4883) as a key mediator of pathological cardiac remodeling. **Therapeutic Potential:** [NPR3](/details-gene/4883) represents a compelling therapeutic target for **inhibition**. Because it clears natriuretic peptides, which have beneficial vasodilatory, natriuretic, and anti-fibrotic effects, blocking [NPR3](/details-gene/4883) would increase the half-life and bioavailability of these endogenous peptides. This strategy is already under investigation for cardiovascular diseases. Development of selective small molecule inhibitors or monoclonal antibodies against [NPR3](/details-gene/4883) could offer a novel therapeutic approach for managing conditions such as hypertension, heart failure, and chronic kidney disease, where augmenting natriuretic peptide signaling is desirable.

Genular Protein ID: 1827804603

Symbol: ANPRC_HUMAN

Name: Atrial natriuretic peptide receptor 3

UniProtKB Accession Codes:

P17342 A2RRD1 B4DT84 E7EPG9

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 3 CDD 2 CTD 1 ChEBI 3 ChEMBL 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 1 EMBL 8 Ensembl 3 EvolutionaryTrace 1 ExpressionAtlas 1 GO 21 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 3 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 4 PDBsum 4 PIR 1 PRINTS 1 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 3 Pumba 1 RNAct 1 RefSeq 3 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 SwissPalm 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 2162522

Title: cDNA sequence of the human atrial natriuretic peptide clearance receptor.

PubMed ID: 2162522

DOI: 10.1093/nar/18.11.3412

PubMed ID: 2169733

Title: Isolation and functional expression of the human atrial natriuretic peptide clearance receptor cDNA.

PubMed ID: 2169733

DOI: 10.1016/0006-291x(90)91216-f

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15372022

Title: The DNA sequence and comparative analysis of human chromosome 5.

PubMed ID: 15372022

DOI: 10.1038/nature02919

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 7727388

Title: The disulfide linkages and glycosylation sites of the human natriuretic peptide receptor-C homodimer.

PubMed ID: 7727388

DOI: 10.1021/bi00203a036

PubMed ID: 1660465

Title: Extracellular domain-IgG fusion proteins for three human natriuretic peptide receptors. Hormone pharmacology and application to solid phase screening of synthetic peptide antisera.

PubMed ID: 1660465

DOI: 10.1016/s0021-9258(18)54463-x

PubMed ID: 11533490

Title: Allosteric activation of a spring-loaded natriuretic peptide receptor dimer by hormone.

PubMed ID: 11533490

DOI: 10.1126/science.1062246

PubMed ID: 16870210

Title: Structural determinants of natriuretic peptide receptor specificity and degeneracy.

PubMed ID: 16870210

DOI: 10.1016/j.jmb.2006.06.060

PubMed ID: 30032985

Title: Bi-allelic Loss-of-Function Mutations in the NPR-C Receptor Result in Enhanced Growth and Connective Tissue Abnormalities.

PubMed ID: 30032985

DOI: 10.1016/j.ajhg.2018.06.007

Sequence Information:

  • Length: 541
  • Mass: 59808
  • Checksum: 8A66415F7F7D62B7
  • Sequence:
    • MPSLLVLTFS PCVLLGWALL AGGTGGGGVG GGGGGAGIGG GRQEREALPP QKIEVLVLLP 
QDDSYLFSLT RVRPAIEYAL RSVEGNGTGR RLLPPGTRFQ VAYEDSDCGN RALFSLVDRV 
AAARGAKPDL ILGPVCEYAA APVARLASHW DLPMLSAGAL AAGFQHKDSE YSHLTRVAPA 
YAKMGEMMLA LFRHHHWSRA ALVYSDDKLE RNCYFTLEGV HEVFQEEGLH TSIYSFDETK 
DLDLEDIVRN IQASERVVIM CASSDTIRSI MLVAHRHGMT SGDYAFFNIE LFNSSSYGDG 
SWKRGDKHDF EAKQAYSSLQ TVTLLRTVKP EFEKFSMEVK SSVEKQGLNM EDYVNMFVEG 
FHDAILLYVL ALHEVLRAGY SKKDGGKIIQ QTWNRTFEGI AGQVSIDANG DRYGDFSVIA 
MTDVEAGTQE VIGDYFGKEG RFEMRPNVKY PWGPLKLRID ENRIVEHTNS SPCKSSGGLE 
ESAVTGIVVG ALLGAGLLMA FYFFRKKYRI TIERRTQQEE SNLGKHRELR EDSIRSHFSV 
A

Genular Protein ID: 3384452133

Symbol: Q60I31_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q60I31

Database IDs:

ARBA 5 AlphaFoldDB 1 Antibodypedia 1 BioGRID-ORCS 1 CDD 2 CTD 1 DNASU 1 DisGeNET 1 EMBL 4 ExpressionAtlas 1 GO 4 Gene3D 1 InterPro 4 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PRINTS 1 PROSITE 1 Pfam 2 PharmGKB 1 RefSeq 1 SAM 2 SMR 1 SUPFAM 1 UCSC 1 VEuPathDB 1

Citations:

PubMed ID: 11181995

Title: The sequence of the human genome.

PubMed ID: 11181995

DOI: 10.1126/science.1058040

Sequence Information:

  • Length: 540
  • Mass: 59767
  • Checksum: 53EE0020A296D6F5
  • Sequence:
    • MPSLLVLTFS PCVLLGWALL AGGTGGGGVG GGGGGAGIGG GRQEREALPP QKIEVLVLLP 
QDDSYLFSLT RVRPAIEYAL RSVEGNGTGR RLLPPGTRFQ VAYEDSDCGN RALFSLVDRV 
AAARGAKPDL ILGPVCEYAA APVARLASHW DLPMLSAGAL AAGFQHKDSE YSHLTRVAPA 
YAKMGEMMLA LFRHHHWSRA ALVYSDDKLE RNCYFTLEGV HEVFQEEGLH TSIYSFDETK 
DLDLEDIVRN IQASERVVIM CASSDTIRSI MLVAHRHGMT SGDYAFFNIE LFNSSSYGDG 
SWKRGDKHDF EAKQAYSSLQ TVTLLRTVKP EFEKFSMEVK SSVEKQGLNM EDYVNMFVEG 
FHDAILLYVL ALHEVLRAGY SKKDGGKIIQ QTWNRTFEGI AGQVSIDANG DRYGDFSVIA 
MTDVEAGTQE VIGDYFGKEG RFEMRPNVKY PWGPLKLRID ENRIVEHTNS SPCKSCGLEE 
SAVTGIVVGA LLGAGLLMAF YFFRKKYRIT IERRTQQEES NLGKHRELRE DSIRSHFSVA

Genular Protein ID: 1004909990

Symbol: A8K4A5_HUMAN

Name: N/A

UniProtKB Accession Codes:

A8K4A5

Database IDs:

ARBA 5 AlphaFoldDB 1 BioGRID-ORCS 1 CDD 2 CTD 1 DNASU 1 DisGeNET 1 EMBL 2 GO 4 Gene3D 1 InterPro 4 KEGG 1 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PRINTS 1 PROSITE 1 PeptideAtlas 1 Pfam 2 RefSeq 1 SAM 2 SUPFAM 1

Sequence Information:

  • Length: 541
  • Mass: 59809
  • Checksum: 8A664152121D62B7
  • Sequence:
    • MPSLLVLTFS PCVLLGWALL AGGTGGGGVG GGGGGAGIGG GRQEREALPP QKIEVLVLLP 
QDDSYLFSLT RVRPAIEYAL RSVEGNGTGR RLLPPGTRFQ VAYEDSDCGN RALFSLVDRV 
AAARGAKPDL ILGPVCEYAA APVARLASHW DLPMLSAGAL AAGFQHKDSE YSHLTRVAPA 
YAKMGEMMLA LFRHHHWSRA ALVYSDDKLE RNCYFTLEGV HEVFQEEGLH TSIYSFDETK 
DLDLEDIVRN IQASERVVIM CASSDTIRSI MLVAHRHGMT SGDYAFFNIE LFNSSSYGDG 
SWKRGDKHDF EAKQAYSSLQ TVTLLRTVKP EFEKFSMEVK SSVEKQGLNM EDYVNMFVEG 
FHDAILLYVL ALHEVLRAGY SKKDGGKIIQ QTWNRTFEGI AGQVSIDANG DRYGDFSVIA 
MTDVEAGTQE VIGDYFGKEG RFEMRPNVKY PWGPLKLRID ENRIVEHTNS SPCKSSGGLE 
ESAVTGIVVG ALLGAGLLMA FYFFRKKYRI TIERRTQQEE SDLGKHRELR EDSIRSHFSV 
A