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Gene Review

NPR1  -  natriuretic peptide receptor 1

Homo sapiens

Synonyms: ANP-A, ANPR-A, ANPRA, ANPa, Atrial natriuretic peptide receptor 1, ...
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Disease relevance of NPR1

  • We conclude that common NPR1 alleles can alter expression of the gene as much as two-fold and could therefore significantly affect genetic risks for essential hypertension and cardiac hypertrophy in humans [1].
  • Novel NPR1 polymorphic variants and its exclusion as a candidate gene for medullary cystic kidney disease (ADMCKD) type 1 [2].
  • Single allele-inactivating mutations in the promoter of human NPR-A are associated with hypertension and heart failure, whereas homozygous inactivating mutations in human NPR-B cause a form of short-limbed dwarfism known as acromesomelic dysplasia type Maroteaux [3].
  • This study constitutes the first demonstration of NPs and NPR mRNAs in human coronary arteries and supports the existence of an autocrine/paracrine NP system that is actively modulated during the progression of atherosclerotic coronary disease [4].
  • Improved NPR-A specificity could provide more effective natriuretic peptides for treatment of acute renal failure or heart failure [5].

High impact information on NPR1

  • We report the hormone-binding thermodynamics and crystal structures at 2.9 and 2.0 angstroms, respectively, of the extracellular domain of the unliganded human NP receptor (NPR-C) and its complex with CNP, a 22-amino acid NP [6].
  • These ANP variants were differentially selected by binding to immobilized natriuretic peptide receptor A (NPR-A) over competing receptor C (NPR-C) in solution [7].
  • Our findings suggest that the kinase homology domain of NPR-A mediates the regulatory action of ATP, not only for signal transduction, but in the modulation of NPR-A hormone affinity [8].
  • Nuclear localization of NPR1 is required for activation of PR gene expression [9].
  • To control the nuclear transport of NPR1, we made a fusion of NPR1 with the glucocorticoid receptor hormone binding domain [9].

Chemical compound and disease context of NPR1


Biological context of NPR1

  • Transient expression analysis in cultured cells of reporter plasmids with the proximal promoter sequences of NPR1 and its 3' untranslated regions showed that these polymorphisms have functional effects [1].
  • While searching for downstream PKG partners using a yeast two-hybrid screen of a human heart cDNA library, we unexpectedly found an upstream association with NPRA [13].
  • Natriuretic peptide receptor A (NPR-A) is an essential cardiovascular regulator that is stimulated by atrial natriuretic peptide and B-type natriuretic peptide, whereas natriuretic peptide receptor B (NPR-B) stimulates long bone growth in a C-type natriuretic peptide-dependent manner [14].
  • AIM: To investigate gene expression of the three NP receptor types (NPR) as well as of the NP in human liver [15].
  • We suggest that mechanisms other than receptor down-regulation account for the desensitization of NPR-A and NPR-B that occurs in response to various physiological and pathological stimuli [16].

Anatomical context of NPR1


Associations of NPR1 with chemical compounds

  • Both genes were responsive to low concentrations of exogenous ABA; an increase in NPR1 RNA could be detected in response to concentrations as low as 10 nM [22].
  • The screening revealed two novel polymorphisms, one intragenic at amino acid position 939, which was occupied by either arginine or glutamine, and a second one located in the 3' prime-UTR, 29 nucleotides downstream of the NPR1 stop codon [2].
  • PKG is a serine/threonine kinase capable of phosphorylating NPRA in vitro; however, regulation of NPRA by PKG has not been previously reported [13].
  • ANP and BNP bind to the natriuretic peptide-A receptor (NPR-A), which, via 3',5'-cyclic guanosine monophosphate (cGMP), mediates natriuresis, vasodilation, renin inhibition, antimitogenesis, and lusitropic properties [23].
  • Responsiveness to the cAMP-dependent vasodilator epoprostenol was similar in WT, eNOS KO and NPR-A KO animals [24].

Physical interactions of NPR1

  • Hence, from a thematic standpoint it is clearly evident that there is a current need to review this subject and provide a consensus forum that establishes the cellular trafficking, sequestration and processing of ANP/NPRA complexes in intact cells [21].
  • On the basis of our results, a molecular model of peptide-bound NPRA was developed by homology modeling with the C-type natriuretic peptide- (CNP-) bound natriuretic peptide receptor C (NPRC) crystal structure [25].

Enzymatic interactions of NPR1

  • Recently, we identified six phosphorylation sites within the kinase homology domain of NPR-A and determined that the conversion of these residues to alanine abolished the ability of the receptor to be phosphorylated or to be activated by ANP and ATP [26].

Regulatory relationships of NPR1

  • CONCLUSION: These data show that NPR transcripts are coexpressed with ANP and CNP mRNA in the human liver [15].

Other interactions of NPR1

  • METHODS: Presence of mRNA coding for all three NPR and for ANP, brain and C-type natriuretic peptide (BNP, CNP) was investigated by reverse transcription-polymerase chain reaction (RT-PCR) [15].
  • These are of three subtypes NPR-A, NPR-B, and NPR-C [27].
  • No difference in the expression of NP receptors relative to GAPDH mRNA of tumorous and non-tumorous tissue was observed except of slightly increased NPR-A transcripts [15].
  • Based on these findings it is unlikely that NPR1 is the same as the MCKD1 gene, although it is presently unknown whether it plays a disease modifying role [2].
  • The juxtamembrane residues C428 and C431 are involved in homodimer formation, confirmed by site-directed mutagenesis of full-length NPR [28].

Analytical, diagnostic and therapeutic context of NPR1

  • RESULTS: Specific PCR products for all three NPR, namely NPR-A, B, and C, could be detected [15].
  • CONCLUSIONS: Significant changes in peptide and receptor expression occur during cell culture and may be integrally linked, with functionally active NPR-A and -B occurring in response to an increase in the expression of the natriuretic peptides possibly acting at the NPR-C [29].
  • Western blots revealed that for the first time natriuretic peptide receptors (NPR) A- and C- were present in prostate cancer cells [30].
  • To identify additional regulatory nodes in the SAR network, we performed microarray analysis on Arabidopsis plants expressing the NPR1-GR (glucocorticoid receptor) fusion protein [31].
  • Monoclonal antibody immunoprecipitation of 35S-labeled proteins revealed NPR-A size heterogeneity, with 135- and 125-kDa species [32].


  1. Common variations in noncoding regions of the human natriuretic peptide receptor A gene have quantitative effects. Knowles, J.W., Erickson, L.M., Guy, V.K., Sigel, C.S., Wilder, J.C., Maeda, N. Hum. Genet. (2003) [Pubmed]
  2. Novel NPR1 polymorphic variants and its exclusion as a candidate gene for medullary cystic kidney disease (ADMCKD) type 1. Koptides, M., Mean, R., Stavrou, C., Pierides, A., Demetriou, K., Nakayama, T., Hildebrandt, F., Fuchshuber, A., Deltas, C.C. Mol. Cell. Probes (2001) [Pubmed]
  3. Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Potter, L.R., Abbey-Hosch, S., Dickey, D.M. Endocr. Rev. (2006) [Pubmed]
  4. Natriuretic peptide system gene expression in human coronary arteries. Casco, V.H., Veinot, J.P., Kuroski de Bold, M.L., Masters, R.G., Stevenson, M.M., de Bold, A.J. J. Histochem. Cytochem. (2002) [Pubmed]
  5. Novel analog of atrial natriuretic peptide selective for receptor-A produces increased diuresis and natriuresis in rats. Jin, H., Li, B., Cunningham, B., Tom, J., Yang, R., Sehl, P., Thomas, G.R., Ko, A., Oare, D., Lowe, D.G. J. Clin. Invest. (1996) [Pubmed]
  6. Allosteric activation of a spring-loaded natriuretic peptide receptor dimer by hormone. He Xl, n.u.l.l., Chow Dc, n.u.l.l., Martick, M.M., Garcia, K.C. Science (2001) [Pubmed]
  7. Production of an atrial natriuretic peptide variant that is specific for type A receptor. Cunningham, B.C., Lowe, D.G., Li, B., Bennett, B.D., Wells, J.A. EMBO J. (1994) [Pubmed]
  8. Hormonal induction of low affinity receptor guanylyl cyclase. Jewett, J.R., Koller, K.J., Goeddel, D.V., Lowe, D.G. EMBO J. (1993) [Pubmed]
  9. Nuclear localization of NPR1 is required for activation of PR gene expression. Kinkema, M., Fan, W., Dong, X. Plant Cell (2000) [Pubmed]
  10. Renal atrial natriuretic peptide receptors binding properties and function are resistant to DOCA-salt-induced hypertension in rats. Woodard, G.E., Li, X., Rosado, J.A. Regul. Pept. (2007) [Pubmed]
  11. Human A-type ANP receptor upregulation by PACAP and carbachol in neuroblastoma cells. Forgeur, A., Svoboda, M., Winand, J., Robberecht, P., Delporte, C. Mol. Cell. Endocrinol. (1999) [Pubmed]
  12. Staphylococcus aureus pathogenicity on Arabidopsis thaliana is mediated either by a direct effect of salicylic acid on the pathogen or by SA-dependent, NPR1-independent host responses. Prithiviraj, B., Bais, H.P., Jha, A.K., Vivanco, J.M. Plant J. (2005) [Pubmed]
  13. Atrial natriuretic peptide induces natriuretic peptide receptor-cGMP-dependent protein kinase interaction. Airhart, N., Yang, Y.F., Roberts, C.T., Silberbach, M. J. Biol. Chem. (2003) [Pubmed]
  14. ATP-independent activation of natriuretic peptide receptors. Antos, L.K., Abbey-Hosch, S.E., Flora, D.R., Potter, L.R. J. Biol. Chem. (2005) [Pubmed]
  15. Differential gene expression of the three natriuretic peptides and natriuretic peptide receptor subtypes in human liver. Vollmar, A.M., Paumgartner, G., Gerbes, A.L. Gut (1997) [Pubmed]
  16. Down-regulation does not mediate natriuretic peptide-dependent desensitization of natriuretic peptide receptor (NPR)-A or NPR-B: guanylyl cyclase-linked natriuretic peptide receptors do not internalize. Fan, D., Bryan, P.M., Antos, L.K., Potthast, R.J., Potter, L.R. Mol. Pharmacol. (2005) [Pubmed]
  17. Gastric atrial natriuretic peptide regulates endocrine secretion in antrum and fundus of human and rat stomach. Gower, W.R., Premaratne, S., McCuen, R.W., Arimura, A., McAfee, Q., Schubert, M.L. Am. J. Physiol. Gastrointest. Liver Physiol. (2003) [Pubmed]
  18. Chromosomal distribution of three members of the human natriuretic peptide receptor/guanylyl cyclase gene family. Lowe, D.G., Klisak, I., Sparkes, R.S., Mohandas, T., Goeddel, D.V. Genomics (1990) [Pubmed]
  19. The H295R human adrenocortical cell line contains functional atrial natriuretic peptide receptors that inhibit aldosterone biosynthesis. Bodart, V., Rainey, W.E., Fournier, A., Ong, H., De Léan, A. Mol. Cell. Endocrinol. (1996) [Pubmed]
  20. Production and characterization of monoclonal antibodies against human natriuretic peptide receptor-A or -B. Kitano, K., Fukuda, Y., Nagahira, K., Nasu, T., Izumi, R., Kawashima, K., Nakanishi, T. Immunol. Lett. (1995) [Pubmed]
  21. Intracellular trafficking and metabolic turnover of ligand-bound guanylyl cyclase/atrial natriuretic peptide receptor-A into subcellular compartments. Pandey, K.N. Mol. Cell. Biochem. (2002) [Pubmed]
  22. NPR genes, which are negatively regulated by phytochrome action in Lemna gibba L. G-3, can also be positively regulated by abscisic acid. Williams, S.A., Weatherwax, S.C., Bray, E.A., Tobin, E.M. Plant Physiol. (1994) [Pubmed]
  23. The natriuretic peptides in heart failure: diagnostic and therapeutic potentials. Chen, H.H., Burnett, J.C. Proc. Assoc. Am. Physicians (1999) [Pubmed]
  24. Reciprocal regulation of human soluble and particulate guanylate cyclases in vivo. Madhani, M., Okorie, M., Hobbs, A.J., Macallister, R.J. Br. J. Pharmacol. (2006) [Pubmed]
  25. Photolabeling study of the ligand binding domain of natriuretic peptide receptor A: development of a model. Jossart, C., Coupal, M., McNicoll, N., Fournier, A., Wilkes, B.C., De Léan, A. Biochemistry (2005) [Pubmed]
  26. A constitutively "phosphorylated" guanylyl cyclase-linked atrial natriuretic peptide receptor mutant is resistant to desensitization. Potter, L.R., Hunter, T. Mol. Biol. Cell (1999) [Pubmed]
  27. Natriuretic peptide receptor-C signaling and regulation. Anand-Srivastava, M.B. Peptides (2005) [Pubmed]
  28. The disulfide linkages and glycosylation sites of the human natriuretic peptide receptor-C homodimer. Stults, J.T., O'Connell, K.L., Garcia, C., Wong, S., Engel, A.M., Garbers, D.L., Lowe, D.G. Biochemistry (1994) [Pubmed]
  29. Differential expression and synthesis of natriuretic peptides determines natriuretic peptide receptor expression in primary cultures of human proximal tubular cells. Mistry, S.K., Hawksworth, G.M., Struthers, A.D., McLay, J.S. J. Hypertens. (2001) [Pubmed]
  30. Four peptide hormones' specific decrease (up to 97%) of human prostate carcinoma cells. Vesely, B.A., Alli, A.A., Song, S.J., Gower, W.R., Sanchez-Ramos, J., Vesely, D.L. Eur. J. Clin. Invest. (2005) [Pubmed]
  31. A genomic approach to identify regulatory nodes in the transcriptional network of systemic acquired resistance in plants. Wang, D., Amornsiripanitch, N., Dong, X. PLoS Pathog. (2006) [Pubmed]
  32. Human natriuretic peptide receptor-A guanylyl cyclase. Hormone cross-linking and antibody reactivity distinguish receptor glycoforms. Lowe, D.G., Fendly, B.M. J. Biol. Chem. (1992) [Pubmed]
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