NPR1

Summary

NPR1 (natriuretic peptide receptor 1, HGNC:7943) is a protein-coding gene on chromosome 1q21.3, encoding Atrial natriuretic peptide receptor 1 (P16066). Receptor for the atrial natriuretic peptide NPPA/ANP and the brain natriuretic peptide NPPB/BNP which are potent vasoactive hormones playing a key role in cardiovascular homeostasis.

Guanylyl cyclases, catalyzing the production of cGMP from GTP, are classified as soluble and membrane forms (Garbers and Lowe, 1994 [PubMed 7982997]). The membrane guanylyl cyclases, often termed guanylyl cyclases A through F, form a family of cell-surface receptors with a similar topographic structure: an extracellular ligand-binding domain, a single membrane-spanning domain, and an intracellular region that contains a protein kinase-like domain and a cyclase catalytic domain. GC-A and GC-B function as receptors for natriuretic peptides; they are also referred to as atrial natriuretic peptide receptor A (NPR1) and type B (NPR2; MIM 108961). Also see NPR3 (MIM 108962), which encodes a protein with only the ligand-binding transmembrane and 37-amino acid cytoplasmic domains. NPR1 is a membrane-bound guanylate cyclase that serves as the receptor for both atrial and brain natriuretic peptides (ANP (MIM 108780) and BNP (MIM 600295), respectively).

Source: NCBI Gene 4881 — RefSeq curated summary.

At a glance

• Gene–disease (curated): genetic hypertension (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 110 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000906

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7943
Approved symbol	NPR1
Name	natriuretic peptide receptor 1
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Aliases	GUCY2A, ANPa
Ensembl gene	ENSG00000169418
Ensembl biotype	protein_coding
OMIM	108960
Entrez	4881

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 15 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000368677, ENST00000368680, ENST00000413826, ENST00000908786, ENST00000908787, ENST00000908788, ENST00000908789, ENST00000908790, ENST00000932961, ENST00000955924, ENST00000955925, ENST00000955926, ENST00000955927, ENST00000955928, ENST00000955929, ENST00000955930, ENST00000955931

RefSeq mRNA: 1 — MANE Select: NM_000906 NM_000906

CCDS: CCDS1051

Canonical transcript exons

ENST00000368680 — 22 exons

Exon	Start	End
ENSE00001176536	153693106	153693197
ENSE00001447739	153693352	153693992
ENSE00001610755	153687200	153687356
ENSE00001617587	153684964	153685084
ENSE00001646348	153682498	153682589
ENSE00001672342	153681180	153681293
ENSE00001674375	153683740	153683824
ENSE00001725104	153688053	153688221
ENSE00001747086	153681704	153681839
ENSE00001747848	153680501	153680700
ENSE00001749106	153688953	153689099
ENSE00001765269	153686123	153686200
ENSE00001766758	153687634	153687789
ENSE00001775488	153686646	153686750
ENSE00001780748	153687016	153687087
ENSE00001794899	153685806	153685880
ENSE00001800621	153683376	153683511
ENSE00002311377	153678688	153679829
ENSE00003695921	153689453	153689521
ENSE00003699353	153689188	153689311
ENSE00003699542	153690284	153690382
ENSE00003701234	153689806	153689980

Expression profiles

Bgee: expression breadth ubiquitous, 243 present calls, max score 98.27.

FANTOM5 (CAGE): breadth broad, TPM avg 7.8070 / max 356.2964, expressed in 761 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
5427	2.4203	528
5428	1.9206	307
5430	1.6737	334
5429	1.0135	248
5431	0.2862	139
5433	0.2335	106
5432	0.1683	95
5426	0.0606	23
201741	0.0229	9
5425	0.0074	2

Top tissues by expression

277 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
descending thoracic aorta	UBERON:0002345	98.27	gold quality
thoracic aorta	UBERON:0001515	98.24	gold quality
ascending aorta	UBERON:0001496	98.22	gold quality
right uterine tube	UBERON:0001302	96.68	gold quality
omental fat pad	UBERON:0010414	96.18	gold quality
peritoneum	UBERON:0002358	96.16	gold quality
adipose tissue of abdominal region	UBERON:0007808	95.91	gold quality
olfactory bulb	UBERON:0002264	95.44	silver quality
mucosa of stomach	UBERON:0001199	95.26	gold quality
left uterine tube	UBERON:0001303	94.81	gold quality
right coronary artery	UBERON:0001625	94.80	gold quality
type B pancreatic cell	CL:0000169	94.76	silver quality
left coronary artery	UBERON:0001626	94.41	gold quality
coronary artery	UBERON:0001621	94.31	gold quality
metanephros cortex	UBERON:0010533	93.90	gold quality
subcutaneous adipose tissue	UBERON:0002190	93.35	gold quality
adipose tissue	UBERON:0001013	93.21	gold quality
right lung	UBERON:0002167	93.14	gold quality
triceps brachii	UBERON:0001509	92.89	silver quality
gluteal muscle	UBERON:0002000	92.71	silver quality
aorta	UBERON:0000947	92.60	gold quality
right ovary	UBERON:0002118	92.49	gold quality
connective tissue	UBERON:0002384	92.42	gold quality
decidua	UBERON:0002450	92.35	gold quality
upper lobe of left lung	UBERON:0008952	91.72	gold quality
left ovary	UBERON:0002119	91.19	gold quality
upper lobe of lung	UBERON:0008948	91.10	gold quality
apex of heart	UBERON:0002098	90.78	gold quality
pericardium	UBERON:0002407	90.62	gold quality
blood vessel layer	UBERON:0004797	90.43	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	20.63

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
PGR

Upstream regulators (CollecTRI, top): CEBPA, ETS1, FOXA2, FOXP3, GATA1, IKZF1, KAT7, NFYA, NKX2-5, NR5A1, PITX2, RARA, SP1, SP3, SRY, USF1, VDR

miRNA regulators (miRDB)

34 targeting NPR1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-4708-3P	99.51	67.99	870
HSA-MIR-6128	99.33	67.83	1581
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-6754-3P	98.84	66.60	889
HSA-MIR-6728-3P	98.63	67.63	1534
HSA-MIR-6811-3P	98.62	66.54	944
HSA-MIR-767-3P	98.61	67.69	1192
HSA-MIR-934	98.49	70.44	581
HSA-MIR-4257	97.86	68.05	1190
HSA-MIR-146B-3P	97.83	65.29	782
HSA-MIR-1271-3P	97.56	64.85	865
HSA-MIR-550A-3-5P	97.56	65.35	823
HSA-MIR-550A-5P	97.56	65.35	823
HSA-MIR-3121-5P	97.30	66.62	1146

Literature-anchored findings (GeneRIF, showing 40)

• kinetics of internalization, trafficking, and down-regulation of recombinant guanylyl cyclase/natriuretic peptide receptor-A (NPRA) (PMID:11704663)
• unlikely that NPR1 is the same as the MCKD1 gene, mutations in which cause the adult form of medullary cystic kidney disease type 1; however, it is presently unknown whether it plays a disease modifying role (PMID:11851379)
• This gene codes for natriuretic peptide receptor A, which mediates natriuretic, diuretic, and vasorelaxing actions of the natriuretic peptides. (PMID:12483301)
• The “deletion 15129” variant might participate in the functional impairment of natriuretic peptide system defining and increased genetic susceptibility to hypertension. (PMID:12506509)
• activation stabilizes a membrane-distal dimer interface (PMID:12547834)
• Human dendritic cells, but not monocytes, express functional ANP receptor GC-A at both mRNA and protein levels. (PMID:12794112)
• NPRA-PKG association may have a role in compartmentation of cGMP-mediated signaling and regulation of receptor sensitivity (PMID:12855709)
• The novel Npr1 gene 3C variant and the Npr3 gene C(-55) allele are associated with hypertensive family history (PMID:12872042)
• the M341I missense mutation is associated with risk of myocardial infarct (MI) and may be a genetic marker of MI (PMID:14646971)
• NPR-A and NPR-B are desensitized in cells in which they are not internalized. (PMID:15459247)
• discussion of experimental insights into the mechanisms that cells utilize in modulating the delivery and metabolic processing of ligand-bound NPRA into the cell interior [review] (PMID:15911067)
• discussion of the functional significance of the promoter region of Npr1 gene and its transcriptional regulation [review] (PMID:15911069)
• ATP does not activate NPRA and NPRB as has been repeatedly reported. Instead, ATP increases activity primarily by maintaining proper receptor phosphorylation status but also serves a previously unappreciated enzyme stabilizing function. (PMID:15911610)
• interaction of atrial natriuretic peptide with natriuretic peptide receptor-A modulates the binding of ATP to the kinase homology domain (PMID:16262696)
• NPR-A protein localized to cardiomyocytes, endocardial endothelial cells, and smooth muscle of intramyocardial vessels; downregulation in the density of NPR-A in heart and coronary was observed in artery of patients with ischemic heart disease (PMID:16778132)
• ANP/NPRA system significantly contributes to ventricular remodeling in human essential hypertension. (PMID:16875975)
• Data suggest that natriuretic peptide receptor A (NPR-A) interacts with fibronectin to enhance brain natriuretic peptide (BNP) activation of cyclic GMP and that a small NPR-A-specific RGD peptide augments this action of BNP. (PMID:16986166)
• Nppa and Npr1 gene polymorphisms are not associated with normal-tension glaucoma, suggesting that this gene does not have an important role in the pathogenesis of optic neuropathy in this disease. (PMID:17460430)
• In patients with Dukes stage C/D colorectal cancer, the Cox Proportional Hazard Model analysis demonstrated a significant association between increased patient survival and low expression of ITGB2 (p = 0.011) and NPR1 (p = 0.023) genes. (PMID:18306933)
• Real-time PCR revealed that large adipocytes expressed higher mRNA levels of NPRA, and binding studies showed that large adipocytes expressed more NPR-A on the membrane than small adipocytes. (PMID:18383440)
• The “4-minus” haplotype of the NPR-A receptor gene is associated with high NT-proBNP values and is a genetic determinant of the interindividual variability in the BNP system in healthy individuals but probably not in patients with cardiovascular disease. (PMID:18436476)
• alternative splicing can regulate endogenous ANP/GC-A signaling (PMID:18713751)
• In the present study conducted in a homogeneous Hellenic population, no associations between Angiotensinogen,angiotensin-converting enzyme, and NPRA gene polymorphisms and hypertension were found. (PMID:19126660)
• Adipose tissue blood flow responsiveness to nutrient intake is related to the transcription of two genes expressed in adipose tissue and directly involved in vasodilatory actions (eNOS and NPRA). (PMID:19165164)
• Data indicate that the familial ANP mutation associated with atrial fibrillation has only minor effects on natriuretic peptide receptor interactions but markedly modifies peptide proteolysis. (PMID:19458086)
• These results indicate that the ANP/GC-A system is involved in immune regulation through plasmacytoid dendritic cells in secondary lymphoid organs. (PMID:19563399)
• Results show that NOGCbeta1 and GC-A interact and that NOGCbeta1 regulates atrial natriuretic peptide signaling in HK-2 cells. (PMID:20024606)
• Midregional pro-A-type natriuretic peptide has a comparable accuracy to brain natriuretic peptide BNP for evaluation of cardiocirculatory exercise limitation. (PMID:20034689)
• The SS genotype of the AGT gene was related with an increased risk for 3-vessel CAD (PMID:20529973)
• The data indicates that ANP, BNP, and CNP and natriuretic peptide receptor transcripts are expressed and are functional in human lens epithelial cells. (PMID:20700369)
• we identified and characterized new phosphorylation sites in GC-A and GC-B and provide the first evidence of phosphorylation sites within human guanylyl cyclases. (PMID:20977274)
• Cellular exposure to Go6976 reduced basal and natriuretic peptide-dependent, but not detergent-dependent, GC-A and GC-B activity. (PMID:21366551)
• review attempts to provide insights and to delineate the current concepts in the field of functional genomics and signaling of GC-A/NPRA in hypertension and cardiovascular disease states at the molecular level (PMID:21375691)
• NPRA promotes prostate cancer development in part by regulating macrophage migration inhibitory factor (PMID:21586128)
• Go6976 reduces GTP binding to the catalytic site of GC-A and GC-B and that ATP increases the magnitude of the inhibition. (PMID:21828054)
• Results demonstrate the opposite effects of NPR-A and NPR-C in LPS-mediated endothelial permeability and lung injury. (PMID:22001395)
• human ventricular cardiomyocytes express low levels of GC-A and GC-A in cardiomyocytes from failing human hearts is refractory to ANP stimulation. (PMID:22133375)
• Guanylyl cyclases A and B are asymmetric dimers that are allosterically activated by ATP binding to the catalytic domain. (PMID:22949736)
• ACNP stimulated both human natriuretic peptide receptors (NPRs), NPRA and NPRB, as potent as their native ligands in receptor transfected cells. (PMID:23186809)
• Molecular dynamics analysis indicated decreases in the values of Van der Waals, electrostatic energy and potential energy of NPRB/Vasonatrin peptide compared to NPRA/Vasonatrin peptide. (PMID:24699414)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	npr2	ENSDARG00000104393
mus_musculus	Npr1	ENSMUSG00000027931
rattus_norvegicus	Npr1	ENSRNOG00000014684
drosophila_melanogaster	CG31183	FBGN0051183
caenorhabditis_elegans	gcy-28	WBGENE00020131

Paralogs (17): GUCY1B1 (ENSG00000061918), GUCY2C (ENSG00000070019), ADCY2 (ENSG00000078295), GUCY2F (ENSG00000101890), NPR3 (ENSG00000113389), ADCY7 (ENSG00000121281), ADCY4 (ENSG00000129467), GUCY2D (ENSG00000132518), ADCY3 (ENSG00000138031), GUCY1A2 (ENSG00000152402), ADCY8 (ENSG00000155897), NPR2 (ENSG00000159899), ADCY9 (ENSG00000162104), GUCY1A1 (ENSG00000164116), ADCY1 (ENSG00000164742), ADCY5 (ENSG00000173175), ADCY6 (ENSG00000174233)

Protein

Protein identifiers

Atrial natriuretic peptide receptor 1 — P16066 (reviewed: P16066)

Alternative names: Atrial natriuretic peptide receptor type A, Guanylate cyclase A

All UniProt accessions (2): A0A140VJE6, P16066

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for the atrial natriuretic peptide NPPA/ANP and the brain natriuretic peptide NPPB/BNP which are potent vasoactive hormones playing a key role in cardiovascular homeostasis. Plays an essential role in the regulation of endothelial cell senescence and vascular aging. Upon activation by ANP or BNP, stimulates the production of cyclic guanosine monophosphate (cGMP) that promotes vascular tone and volume homeostasis by activation of protein kinase cGMP-dependent 1/PRKG1 and subsequently PRKAA1, thereby controlling blood pressure and maintaining cardiovascular homeostasis.

Subunit / interactions. Homodimer.

Subcellular location. Membrane.

Post-translational modifications. Phosphorylation of the protein kinase-like domain is required for full activation by ANP.

Induction. Expression is chronologically prohibited with ages.

Similarity. Belongs to the adenylyl cyclase class-4/guanylyl cyclase family.

RefSeq proteins (1): NP_000897* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001054	A/G_cyclase	Domain
IPR001170	ANPR/GUC	Family
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR001828	ANF_lig-bd_rcpt	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR018297	A/G_cyclase_CS	Conserved_site
IPR028082	Peripla_BP_I	Homologous_superfamily
IPR029787	Nucleotide_cyclase	Homologous_superfamily
IPR050401	Cyclic_nucleotide_synthase	Family

Pfam: PF00211, PF01094, PF07714

Enzyme classification (BRENDA):

• EC 4.6.1.2 — guanylate cyclase (BRENDA: 58 organisms, 213 substrates, 212 inhibitors, 100 Km, 16 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GTP	0.01–6.09	90
2’-O-(N-METHYLANTHRANILOYL) GUANOSINE 5’-TRIPHOS	0.0357	1
GUANYL-(BETA,GAMMA-METHYLENE)-DIPHOSPHONATE	0.37	1
GUANYL-IMIDODIPHOSPHATE	0.07	1
MN2+	2.7	1

Catalyzed reactions (Rhea), 1 shown:

• GTP = 3’,5’-cyclic GMP + diphosphate (RHEA:13665)

UniProt features (92 total): strand 31, helix 22, modified residue 7, glycosylation site 7, turn 6, sequence variant 5, disulfide bond 3, binding site 3, topological domain 2, domain 2, signal peptide 1, chain 1, transmembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
9DZF	ELECTRON MICROSCOPY	2.7
9DZJ	ELECTRON MICROSCOPY	2.7
9BCL	ELECTRON MICROSCOPY	2.9
9BCN	ELECTRON MICROSCOPY	2.9
9DZK	ELECTRON MICROSCOPY	2.9
9DZH	ELECTRON MICROSCOPY	3
8TG9	ELECTRON MICROSCOPY	3.08
9BCQ	ELECTRON MICROSCOPY	3.1
9BCV	ELECTRON MICROSCOPY	3.2
9DZG	ELECTRON MICROSCOPY	3.3
8TGA	ELECTRON MICROSCOPY	3.65
9BCP	ELECTRON MICROSCOPY	4.1
9BCO	ELECTRON MICROSCOPY	4.4
9BCS	ELECTRON MICROSCOPY	4.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P16066-F1	84.82	0.55

Antibody-complex structures (SAbDab): 2 — 8TG9, 8TGA

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (3): 85; 117; 118

Post-translational modifications (7): 519, 529, 532, 534, 538, 542, 545

Disulfide bonds (3): 92–118, 196–245, 455–464

Glycosylation sites (7): 34, 45, 212, 338, 379, 386, 427

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-5578768	Physiological factors
R-HSA-397014	Muscle contraction
R-HSA-5576891	Cardiac conduction

MSigDB gene sets: 188 (showing top): GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_EXCRETION, BENPORATH_ES_WITH_H3K27ME3, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_NEGATIVE_REGULATION_OF_SMOOTH_MUSCLE_CELL_PROLIFERATION, GOBP_CIRCULATORY_SYSTEM_PROCESS, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GOBP_CGMP_BIOSYNTHETIC_PROCESS, MODULE_445, GOBP_GROWTH, MODULE_65, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_CYCLIC_NUCLEOTIDE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS

GO Biological Process (20): cGMP biosynthetic process (GO:0006182), cell surface receptor signaling pathway (GO:0007166), receptor guanylyl cyclase signaling pathway (GO:0007168), body fluid secretion (GO:0007589), regulation of blood pressure (GO:0008217), obsolete positive regulation of cGMP-mediated signaling (GO:0010753), negative regulation of angiogenesis (GO:0016525), obsolete cGMP-mediated signaling (GO:0019934), negative regulation of cell growth (GO:0030308), positive regulation of urine volume (GO:0035810), positive regulation of renal sodium excretion (GO:0035815), dopamine metabolic process (GO:0042417), regulation of vascular permeability (GO:0043114), negative regulation of smooth muscle cell proliferation (GO:0048662), blood vessel diameter maintenance (GO:0097746), protein phosphorylation (GO:0006468), G protein-coupled receptor signaling pathway (GO:0007186), blood circulation (GO:0008015), cyclic nucleotide biosynthetic process (GO:0009190), intracellular signal transduction (GO:0035556)

GO Molecular Function (12): peptide receptor activity (GO:0001653), guanylate cyclase activity (GO:0004383), protein kinase activity (GO:0004672), ATP binding (GO:0005524), GTP binding (GO:0005525), G protein-coupled peptide receptor activity (GO:0008528), natriuretic peptide receptor activity (GO:0016941), peptide hormone binding (GO:0017046), hormone binding (GO:0042562), nucleotide binding (GO:0000166), lyase activity (GO:0016829), phosphorus-oxygen lyase activity (GO:0016849)

GO Cellular Component (4): plasma membrane (GO:0005886), signaling receptor complex (GO:0043235), ANPR-A receptor complex (GO:1990620), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Cardiac conduction	1
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	3
blood circulation	3
regulation of biological quality	2
vascular process in circulatory system	2
G protein-coupled receptor activity	2
purine ribonucleoside triphosphate binding	2
peptide receptor activity	2
purine ribonucleotide biosynthetic process	1
cyclic nucleotide biosynthetic process	1
cGMP metabolic process	1
enzyme-linked receptor protein signaling pathway	1
secretion	1
regulation of body fluid levels	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
negative regulation of cellular process	1
regulation of urine volume	1
renal sodium excretion	1
regulation of renal sodium excretion	1
positive regulation of secretion	1
positive regulation of multicellular organismal process	1
catecholamine metabolic process	1
negative regulation of cell population proliferation	1
smooth muscle cell proliferation	1
regulation of smooth muscle cell proliferation	1
regulation of tube diameter	1
phosphorylation	1
protein modification process	1
circulatory system process	1
nucleotide biosynthetic process	1
cyclic nucleotide metabolic process	1
intracellular anatomical structure	1
signaling receptor activity	1
peptide binding	1
cGMP biosynthetic process	1
cyclase activity	1

Protein interactions and networks

STRING

1274 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NPR1	NPPA	P01160	999
NPR1	NPPB	P16860	996
NPR1	NPPC	P23582	940
NPR1	NPTXR	O95502	848
NPR1	SEMA3A	Q14563	811
NPR1	PLXNA1	Q9UIW2	723
NPR1	PRKG1	P14619	697
NPR1	PGC	P20142	686
NPR1	NPY	P01303	684
NPR1	NPY5R	Q15761	682
NPR1	GCDH	Q92947	678
NPR1	MME	P08473	671
NPR1	MMEL1	Q495T6	662
NPR1	FMO5	P49326	653
NPR1	CASQ2	O14958	649

IntAct

10 interactions, top by confidence:

A	B	Type	Score
Ndc80	RRBP1	psi-mi:“MI:0915”(physical association)	0.400
ATF7IP	NPR1	psi-mi:“MI:0915”(physical association)	0.370
NPR1	PSEN1	psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
AFG2B	MMP24OS	psi-mi:“MI:0914”(association)	0.350
BFSP2	ZZEF1	psi-mi:“MI:0914”(association)	0.350
DYNLT4	NPR1	psi-mi:“MI:0914”(association)	0.350
SLC27A6	NBAS	psi-mi:“MI:0914”(association)	0.350
SLC35C1	ADCY3	psi-mi:“MI:0914”(association)	0.350

BioGRID (20): NPR1 (Biochemical Activity), NPR1 (Negative Genetic), NPR1 (Negative Genetic), TXN (Negative Genetic), NPR1 (Negative Genetic), NPR1 (Protein-RNA), NPR1 (Reconstituted Complex), NPPB (Reconstituted Complex), NPR1 (Two-hybrid), NPR1 (Negative Genetic), NPR1 (Proximity Label-MS), NPR1 (Affinity Capture-MS), NPR1 (Affinity Capture-MS), NPR1 (Affinity Capture-MS), PARL (Affinity Capture-MS)

ESM2 similar proteins: A0A061IR73, A0A0U1RPR8, O02740, O08644, O09127, O15197, O19179, O43542, P0C0K6, P0C0K7, P16066, P16067, P20594, P21709, P26770, P29317, P29322, P35590, P46197, P51839, P51840, P51976, P52785, P52824, P54753, P54754, P54760, P54761, P55203, P55205, Q02846, Q03146, Q06805, Q06806, Q08345, Q08DH8, Q13470, Q3U6U5, Q3UH93, Q5JZY3

Diamond homologs: A0A078BQP2, A0A0U1RPR8, E7EAU8, H2L002, O02298, O02740, O16715, O19179, O54865, O62179, O75343, P0A4Y1, P16065, P16066, P16068, P18293, P18910, P19686, P19687, P20594, P20595, P22717, P23897, P25092, P26770, P33402, P51840, P51841, P51842, P52785, P55202, P55203, P55204, P70106, P90895, P91550, P92006, P9WQ34, P9WQ35, Q02108

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
NPPA	up-regulates	NPR1	binding
NPR1	“up-regulates activity”	ORM1	phosphorylation
NPR1	“down-regulates activity”	ART1	phosphorylation
NPR1	“up-regulates activity”	ORM2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

110 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	80
Likely benign	6
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

3074 predictions. Top by Δscore:

Variant	Effect	Δscore
1:153679826:CGAGG:C	donor_loss	1.0000
1:153679828:AGG:A	donor_loss	1.0000
1:153679829:GGT:G	donor_loss	1.0000
1:153679830:G:GG	donor_gain	1.0000
1:153679830:GTGAG:G	donor_loss	1.0000
1:153681291:CTGG:C	donor_loss	1.0000
1:153681293:GGTA:G	donor_loss	1.0000
1:153681294:G:GA	donor_loss	1.0000
1:153681295:T:G	donor_loss	1.0000
1:153681702:A:AG	acceptor_gain	1.0000
1:153681702:A:T	acceptor_loss	1.0000
1:153681702:AG:A	acceptor_gain	1.0000
1:153681702:AGGT:A	acceptor_gain	1.0000
1:153681703:G:GA	acceptor_gain	1.0000
1:153681703:GG:G	acceptor_gain	1.0000
1:153681703:GGT:G	acceptor_gain	1.0000
1:153681703:GGTG:G	acceptor_gain	1.0000
1:153681703:GGTGA:G	acceptor_gain	1.0000
1:153681838:AGG:A	donor_loss	1.0000
1:153681839:GGTCA:G	donor_loss	1.0000
1:153681840:G:GG	donor_gain	1.0000
1:153681840:GTCAG:G	donor_loss	1.0000
1:153681841:T:G	donor_loss	1.0000
1:153682488:AT:A	acceptor_gain	1.0000
1:153682489:T:G	acceptor_gain	1.0000
1:153682493:CTCA:C	acceptor_loss	1.0000
1:153682494:TCAG:T	acceptor_loss	1.0000
1:153682496:A:AG	acceptor_gain	1.0000
1:153682496:A:T	acceptor_loss	1.0000
1:153682496:AGGT:A	acceptor_gain	1.0000

AlphaMissense

6868 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:153687068:T:C	L639P	1.000
1:153687278:T:C	F672L	1.000
1:153687280:T:A	F672L	1.000
1:153687280:T:G	F672L	1.000
1:153688982:T:C	L816P	1.000
1:153688995:G:A	M820I	1.000
1:153688995:G:C	M820I	1.000
1:153688995:G:T	M820I	1.000
1:153689005:G:C	A824P	1.000
1:153689015:T:C	L827P	1.000
1:153689024:T:C	L830P	1.000
1:153689036:G:C	R834P	1.000
1:153689265:A:T	D881V	1.000
1:153689276:T:C	F885L	1.000
1:153689278:C:A	F885L	1.000
1:153689278:C:G	F885L	1.000
1:153689521:G:C	K919N	1.000
1:153689521:G:T	K919N	1.000
1:153690308:G:A	G986E	1.000
1:153690334:T:C	F995L	1.000
1:153690336:T:A	F995L	1.000
1:153690336:T:G	F995L	1.000
1:153690338:G:A	G996E	1.000
1:153690338:G:T	G996V	1.000
1:153690351:C:A	N1000K	1.000
1:153690351:C:G	N1000K	1.000
1:153685001:T:A	W508R	0.999
1:153685001:T:C	W508R	0.999
1:153686193:T:C	L584P	0.999
1:153686686:G:A	G600E	0.999

dbSNP variants (sampled 300 via entrez): RS1000265339 (1:153693859 C>CT), RS1000281998 (1:153684435 A>G), RS1000559466 (1:153692123 G>A), RS1000607029 (1:153692264 A>G), RS1000686450 (1:153686051 G>A), RS1000718417 (1:153692006 G>C), RS1000843871 (1:153679955 A>G), RS1001635280 (1:153691358 A>G), RS1001658927 (1:153679145 C>A,T), RS1001773353 (1:153685214 C>A,G,T), RS1001968983 (1:153692811 C>G), RS1002194853 (1:153684277 A>G), RS1002600791 (1:153689400 C>CCCCA), RS1003067224 (1:153692539 C>T), RS1003182129 (1:153693947 T>C)

Disease associations

OMIM: gene MIM:108960 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
genetic hypertension	Strong	Autosomal recessive

Mondo (1): (MONDO:0015512)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006228_2	Systolic blood pressure	6.000000e-08
GCST006231_14	Mean arterial pressure	4.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0006340	mean arterial pressure

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1988 (SINGLE PROTEIN), CHEMBL2111337 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 2,267 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL2104386	CARPERITIDE	3	2,267

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — Transmembrane guanylyl cyclases

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
Dendroaspis natriuretic peptide	Agonist	9.7	pKd
A-71915	Antagonist	9.5	pKi
PL-3994	Agonist	9.0	pKi
[Asu7,23’]β-ANP-(7-28)	Antagonist	7.5	pKi
compound 20 [PMID: 37522273]	Agonist	6.29	pEC50

ChEMBL bioactivities

90 potent at pChembl≥5 of 97 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.27	IC50	0.054	nM	CHEMBL3349623
10.03	IC50	0.094	nM	CHEMBL4102000
10.00	Ki	0.1	nM	CHEMBL411542
10.00	EC50	0.1	nM	CARPERITIDE
10.00	EC50	0.1	nM	CHEMBL4090153
10.00	EC50	0.1	nM	CHEMBL4206902
9.60	Ki	0.25	nM	CHEMBL3349651
9.54	IC50	0.29	nM	CHEMBL413432
9.52	Ki	0.3	nM	CHEMBL294263
9.40	Ki	0.4	nM	CHEMBL61383
9.31	Ki	0.49	nM	CHEMBL264744
9.19	Ki	0.65	nM	CHEMBL405854
9.17	EC50	0.68	nM	MiniANP
8.70	EC50	2	nM	CHEMBL4099832
8.31	EC50	4.94	nM	CHEMBL405572
8.24	EC50	5.8	nM	CHEMBL4061575
8.22	IC50	6	nM	CHEMBL1643388
8.09	EC50	8.1	nM	CHEMBL4089697
8.08	EC50	8.28	nM	CHEMBL384862
7.85	AC50	14	nM	CHEMBL6148977
7.72	EC50	19	nM	CHEMBL4097422
7.52	EC50	30.11	nM	CHEMBL439465
7.44	IC50	36	nM	CHEMBL507122
7.44	IC50	36	nM	CHEMBL3349961
7.39	EC50	41	nM	CHEMBL4218179
7.38	AC50	42	nM	CHEMBL6159617
7.33	EC50	46.74	nM	CHEMBL409400
7.28	IC50	52	nM	CHEMBL3349622
7.22	IC50	60	nM	CHEMBL1643389
7.21	Ki	62	nM	CHEMBL59028
7.19	Ki	65	nM	CHEMBL304191
7.18	EC50	65.85	nM	CHEMBL414517
7.18	AC50	66	nM	CHEMBL6168494
7.15	EC50	71	nM	CHEMBL4213559
7.14	EC50	73	nM	CHEMBL4071795
7.14	AC50	72	nM	CHEMBL6164527
7.11	EC50	78	nM	CHEMBL4207138
7.06	Ki	87	nM	CHEMBL415133
7.01	EC50	98	nM	CHEMBL4215510
6.97	EC50	108	nM	CHEMBL413653
6.96	EC50	110	nM	CHEMBL4206652
6.92	IC50	120	nM	CHEMBL4098363
6.77	EC50	170	nM	CHEMBL4073156
6.75	EC50	177	nM	CHEMBL385216
6.73	AC50	185	nM	CHEMBL6168511
6.70	EC50	198.4	nM	CHEMBL408343
6.70	EC50	200	nM	CHEMBL4205804
6.67	EC50	215.2	nM	CHEMBL402664
6.66	EC50	220	nM	CHEMBL4077093
6.66	EC50	220	nM	CHEMBL4210772

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression, increases methylation	3
Benzo(a)pyrene	affects methylation, increases expression	2
lasiocarpine	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
titanium dioxide	increases expression	1
trichostatin A	affects expression, decreases reaction	1
sodium arsenite	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
2-palmitoylglycerol	increases expression	1
bisphenol S	increases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Aspirin	decreases expression	1
Cisplatin	increases expression	1
Dexamethasone	increases expression	1
Estradiol	increases expression	1
Glucose	increases expression	1
Hydralazine	affects cotreatment, increases expression	1
Nickel	affects expression, decreases reaction	1
Niclosamide	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	increases expression	1
Tretinoin	decreases expression	1
Triclosan	increases expression	1
Valproic Acid	increases expression, affects cotreatment	1
Cyclosporine	decreases expression	1
Aflatoxin B1	increases expression	1
Sodium Selenite	decreases expression	1
Okadaic Acid	decreases expression	1
Genistein	increases expression	1

ChEMBL screening assays

23 unique, capped per target: 22 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1647324	Binding	Displacement of [125I]ANP from NPR-A expressed in HeLa cells after 3 hrs by gamma counting	Intramolecular azo-bridge as a cystine disulfide bond surrogate: Somatostatin-14 and brain natriuretic peptide (BNP) analogs. — Bioorg Med Chem
CHEMBL753600	Functional	Production of c-GMP in CHO cells expressing natriuretic peptide receptor (NPR-A) in response to compound	Structure-activity relationships for mini atrial natriuretic peptide by proline-scanning mutagenesis and shortening of peptide backbone. — Bioorg Med Chem Lett

Cellosaurus cell lines

2 cell lines: 1 cancer cell line, 1 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1YW	Abcam HeLa NPR1 KO	Cancer cell line	Female
CVCL_KY63	PathHunter CHO-K1 NPR1 Functional Assay	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.