Details for: NPR2

Gene ID: 4882

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: NPR2

Ensembl ID: ENSG00000159899

Description: natriuretic peptide receptor 2

Cell Significance Landscape

Associated with

Significant Cells

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

  • VIP GABAergic cortical interneuron CL4023016
    CSI 9.67
    rCSI 11.55%
    PRS 98.97
  • sst GABAergic cortical interneuron CL4023017
    CSI 8.23
    rCSI 10.61%
    PRS 99.23
  • sncg GABAergic cortical interneuron CL4023015
    CSI 8.19
    rCSI 13.17%
    PRS 98.86
  • cerebral cortex endothelial cell CL1001602
    CSI 8.14
    rCSI 14.08%
    PRS 99.33
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 7.28
    rCSI 17.69%
    PRS 98.56
  • ependymal cell CL0000065
    CSI 6.79
    rCSI 13.78%
    PRS 97.56
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 6.47
    rCSI 8.05%
    PRS 98.88
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 6.11
    rCSI 23.08%
    PRS 98.71
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 5.74
    rCSI 10.14%
    PRS 98.99
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 4.76
    rCSI 7.98%
    PRS 99.01
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 4.49
    rCSI 14.04%
    PRS 99.12
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 3.69
    rCSI 21.73%
    PRS 98.82
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 3.49
    rCSI 12.58%
    PRS 98.78
  • astrocyte of the cerebral cortex CL0002605
    CSI 2.43
    rCSI 5.45%
    PRS 99.07
  • L6b glutamatergic cortical neuron CL4023038
    CSI 2.21
    rCSI 6.92%
    PRS 98.98

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.

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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 [NPR2](/details-gene/4882) (natriuretic peptide receptor 2) encodes a transmembrane guanylate cyclase that functions as a receptor for C-type natriuretic peptide (CNP). Upon ligand binding, it catalyzes the conversion of GTP to cGMP, initiating a downstream signaling cascade. **Overall**, expression data indicate that [NPR2](/details-gene/4882) is highly significant in the central nervous system, with particularly strong expression in diverse subtypes of cortical interneurons, including [VIP GABAergic cortical interneuron](/details-cell/CL4023016) and [sst GABAergic cortical interneuron](/details-cell/CL4023017), as well as glutamatergic neurons and [cerebral cortex endothelial cell](/details-cell/CL1001602). Clinically, mutations in [NPR2](/details-gene/4882) are linked to skeletal growth disorders, including acromesomelic dysplasia, type Maroteaux ([15146390](https://omim.org/entry/602875)), and certain forms of short stature, as well as overgrowth syndromes ([108961](https://omim.org/entry/108961)), highlighting its critical role in endochondral ossification ([Link](https://doi.org/10.1086/422013)). ## Cellular Roles and Expression Landscape The expression profile of [NPR2](/details-gene/4882) strongly points to a primary role in the mammalian central nervous system, particularly within the cerebral cortex. The gene demonstrates the highest significance scores in multiple classes of inhibitory interneurons, such as [VIP GABAergic cortical interneuron](/details-cell/CL4023016) (CSI: 9.67), [sst GABAergic cortical interneuron](/details-cell/CL4023017) (CSI: 8.23), and [pvalb GABAergic cortical interneuron](/details-cell/CL4023018) (CSI: 6.47). This suggests a fundamental function in regulating inhibitory signaling and cortical circuit dynamics. In addition to its role in inhibitory neurons, [NPR2](/details-gene/4882) is also significantly expressed in excitatory neurons, including [L2/3-6 intratelencephalic projecting glutamatergic neuron](/details-cell/CL4023040) (CSI: 7.28) and [corticothalamic-projecting glutamatergic cortical neuron](/details-cell/CL4023013) (CSI: 3.69). Its prominence in both inhibitory and excitatory neuronal populations indicates it may be involved in modulating the overall excitatory/inhibitory balance within cortical microcircuits. Furthermore, its high significance in non-neuronal cells like [cerebral cortex endothelial cell](/details-cell/CL1001602) (CSI: 8.14) and [ependymal cell](/details-cell/CL0000065) (CSI: 6.79) suggests potential roles in neurovascular coupling, blood-brain barrier regulation, or cerebrospinal fluid homeostasis. ## Pathways and Molecular Function The primary molecular function of the [NPR2](/details-gene/4882) protein is [Natriuretic peptide receptor activity](/details-go/GO:0016941) coupled with intracellular [Guanylate cyclase activity](/details-go/GO:0004383). This function is central to the [Receptor guanylyl cyclase signaling pathway](/details-go/GO:0007168), which results in the synthesis of cGMP ([GO:0006182](https://www.ebi.ac.uk/QuickGO/term/GO:0006182)). This cGMP-mediated signaling cascade underlies the diverse biological processes regulated by [NPR2](/details-gene/4882). Consistent with its clinical associations, functional annotations highlight a crucial role in skeletal development, including [Chondrocyte differentiation](/details-go/GO:0002062), [Chondrocyte proliferation](/details-go/GO:0035988), and [Endochondral ossification](/details-go/GO:0001958). These processes are essential for normal bone growth, and their disruption through [NPR2](/details-gene/4882) mutations leads to skeletal dysplasia ([Link](https://doi.org/10.1086/422013)). Its involvement in cardiovascular homeostasis is supported by annotations for [Regulation of blood pressure](/details-go/GO:0008217) and [Cardiac conduction](/details-pathway/R-HSA-5576891). Furthermore, its high expression in the CNS is substantiated by its annotated roles in [Chemical synaptic transmission](/details-go/GO:0007268), [Axonogenesis involved in innervation](/details-go/GO:0060385), and its localization to the [Synapse](/details-go/GO:0045202) and [Neuron projection](/details-go/GO:0043005). ## Research Directions The functional and expression data for [NPR2](/details-gene/4882) suggest several avenues for future investigation. **Testable Hypotheses:** 1. Given its high significance in a wide array of cortical interneurons, [NPR2](/details-gene/4882)-mediated cGMP signaling likely serves as a critical modulator of inhibitory tone in the cerebral cortex. Alterations in this pathway may contribute to the pathophysiology of neurological disorders characterized by excitatory/inhibitory imbalance, such as epilepsy or certain neurodevelopmental conditions. 2. Based on its established role in skeletal growth ([Link](https://doi.org/10.1210/jc.2013-2142)), it is hypothesized that heterozygous loss-of-function variants in [NPR2](/details-gene/4882) may be an underdiagnosed cause of idiopathic short stature. Conversely, specific gain-of-function mutations may be responsible for a wider spectrum of overgrowth syndromes than currently recognized ([Link](https://doi.org/10.1371/journal.pone.0042180)). **Proposed Experiment:** To test the first hypothesis regarding the role of [NPR2](/details-gene/4882) in regulating cortical inhibitory circuits, a conditional knockout mouse model could be employed. By crossing a floxed-[NPR2](/details-gene/4882) mouse line with specific Cre-driver lines (e.g., Pvalb-Cre or Sst-Cre), the gene can be selectively deleted from distinct interneuron populations. Brain slices from these mice could then be analyzed using whole-cell patch-clamp electrophysiology to measure changes in inhibitory postsynaptic currents (IPSCs) and overall neuronal excitability in pyramidal neurons. This would directly assess the contribution of [NPR2](/details-gene/4882) signaling in specific interneurons to cortical network function. **Therapeutic Potential:** [NPR2](/details-gene/4882) is an excellent candidate for therapeutic intervention due to its nature as a cell surface receptor with a well-defined ligand and downstream pathway. For conditions of haploinsufficiency leading to short stature, therapeutic **activation** using long-acting CNP analogs is a promising strategy that is already under investigation. For overgrowth syndromes caused by gain-of-function mutations, therapeutic **inhibition** would be the goal. This could be achieved by developing specific small molecule antagonists for the receptor or inhibitors of the downstream cGMP-dependent protein kinases. Given its high expression in the CNS, the blood-brain barrier permeability and potential neurological side effects of any systemic therapy targeting [NPR2](/details-gene/4882) must be carefully evaluated.

Genular Protein ID: 2184442868

Symbol: ANPRB_HUMAN

Name: Atrial natriuretic peptide receptor 2

UniProtKB Accession Codes:

P20594 B0ZBF2 B0ZBF3 D3DRP3 D3DRP4 O60871 Q4VAK7 Q5TCV2 Q8TA93 Q9UQ50

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 3 CTD 1 ChEBI 3 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 3 DrugCentral 1 EC 1 EMBL 10 Ensembl 1 ExpressionAtlas 1 GO 61 Gene3D 3 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 10 KEGG 1 MANE-Select 1 MIM 7 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 2 OrthoDB 1 PANTHER 2 PIR 1 PRINTS 1 PRO 1 PROSITE 4 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 3 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 Pumba 1 RNAct 1 Reactome 1 RefSeq 1 Rhea 1 SMART 1 SMR 1 STRING 1 SUPFAM 3 SignaLink 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 2570358

Title: Differential activation by atrial and brain natriuretic peptides of two different receptor guanylate cyclases.

PubMed ID: 2570358

DOI: 10.1038/341068a0

PubMed ID: 10082481

Title: Structure of the type B human natriuretic peptide receptor gene and association of a novel microsatellite polymorphism with essential hypertension.

PubMed ID: 10082481

DOI: 10.1161/01.res.84.5.605

PubMed ID: 10073597

Title: cGMP-dependent and -independent inhibition of a K+ conductance by natriuretic peptides: molecular and functional studies in human proximal tubule cells.

PubMed ID: 10073597

DOI: 10.1681/asn.v103472

PubMed ID: 15164053

Title: DNA sequence and analysis of human chromosome 9.

PubMed ID: 15164053

DOI: 10.1038/nature02465

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: 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: 1672777

Title: Selective activation of the B natriuretic peptide receptor by C-type natriuretic peptide (CNP).

PubMed ID: 1672777

DOI: 10.1126/science.1672777

PubMed ID: 14759258

Title: An unappreciated role for RNA surveillance.

PubMed ID: 14759258

DOI: 10.1186/gb-2004-5-2-r8

PubMed ID: 15146390

Title: Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux.

PubMed ID: 15146390

DOI: 10.1086/422013

PubMed ID: 20977274

Title: Mass spectrometric identification of phosphorylation sites in guanylyl cyclase A and B.

PubMed ID: 20977274

DOI: 10.1021/bi101700e

PubMed ID: 17344846

Title: Patterns of somatic mutation in human cancer genomes.

PubMed ID: 17344846

DOI: 10.1038/nature05610

PubMed ID: 22870295

Title: An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.

PubMed ID: 22870295

DOI: 10.1371/journal.pone.0042180

PubMed ID: 24001744

Title: Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature in patients initially classified as idiopathic short stature.

PubMed ID: 24001744

DOI: 10.1210/jc.2013-2142

PubMed ID: 24471569

Title: Identification and functional characterization of two novel NPR2 mutations in Japanese patients with short stature.

PubMed ID: 24471569

DOI: 10.1210/jc.2013-3525

PubMed ID: 23827346

Title: A human skeletal overgrowth mutation increases maximal velocity and blocks desensitization of guanylyl cyclase-B.

PubMed ID: 23827346

DOI: 10.1016/j.bone.2013.06.024

PubMed ID: 26980729

Title: Catalytically active guanylyl cyclase b requires endoplasmic reticulum-mediated glycosylation, and mutations that inhibit this process cause dwarfism.

PubMed ID: 26980729

DOI: 10.1074/jbc.m115.704015

PubMed ID: 17652215

Title: Intact kinase homology domain of natriuretic peptide receptor-B is essential for skeletal development.

PubMed ID: 17652215

DOI: 10.1210/jc.2007-1101

PubMed ID: 24057292

Title: An activating mutation in the kinase homology domain of the natriuretic peptide receptor-2 causes extremely tall stature without skeletal deformities.

PubMed ID: 24057292

DOI: 10.1210/jc.2013-2358

PubMed ID: 24259409

Title: Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene.

PubMed ID: 24259409

DOI: 10.1002/ajmg.a.36218

Sequence Information:

  • Length: 1047
  • Mass: 117022
  • Checksum: 817FB74D6B31F7EF
  • Sequence:
    • MALPSLLLLV AALAGGVRPP GARNLTLAVV LPEHNLSYAW AWPRVGPAVA LAVEALGRAL 
PVDLRFVSSE LEGACSEYLA PLSAVDLKLY HDPDLLLGPG CVYPAASVAR FASHWRLPLL 
TAGAVASGFS AKNDHYRTLV RTGPSAPKLG EFVVTLHGHF NWTARAALLY LDARTDDRPH 
YFTIEGVFEA LQGSNLSVQH QVYAREPGGP EQATHFIRAN GRIVYICGPL EMLHEILLQA 
QRENLTNGDY VFFYLDVFGE SLRAGPTRAT GRPWQDNRTR EQAQALREAF QTVLVITYRE 
PPNPEYQEFQ NRLLIRARED FGVELGPSLM NLIAGCFYDG ILLYAEVLNE TIQEGGTRED 
GLRIVEKMQG RRYHGVTGLV VMDKNNDRET DFVLWAMGDL DSGDFQPAAH YSGAEKQIWW 
TGRPIPWVKG APPSDNPPCA FDLDDPSCDK TPLSTLAIVA LGTGITFIMF GVSSFLIFRK 
LMLEKELASM LWRIRWEELQ FGNSERYHKG AGSRLTLSLR GSSYGSLMTA HGKYQIFANT 
GHFKGNVVAI KHVNKKRIEL TRQVLFELKH MRDVQFNHLT RFIGACIDPP NICIVTEYCP 
RGSLQDILEN DSINLDWMFR YSLINDLVKG MAFLHNSIIS SHGSLKSSNC VVDSRFVLKI 
TDYGLASFRS TAEPDDSHAL YAKKLWTAPE LLSGNPLPTT GMQKADVYSF GIILQEIALR 
SGPFYLEGLD LSPKEIVQKV RNGQRPYFRP SIDRTQLNEE LVLLMERCWA QDPAERPDFG 
QIKGFIRRFN KEGGTSILDN LLLRMEQYAN NLEKLVEERT QAYLEEKRKA EALLYQILPH 
SVAEQLKRGE TVQAEAFDSV TIYFSDIVGF TALSAESTPM QVVTLLNDLY TCFDAIIDNF 
DVYKVETIGD AYMVVSGLPG RNGQRHAPEI ARMALALLDA VSSFRIRHRP HDQLRLRIGV 
HTGPVCAGVV GLKMPRYCLF GDTVNTASRM ESNGQALKIH VSSTTKDALD ELGCFQLELR 
GDVEMKGKGK MRTYWLLGER KGPPGLL