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Gene Review

NPR3  -  natriuretic peptide receptor 3

Homo sapiens

Synonyms: ANP-C, ANPR-C, ANPRC, Atrial natriuretic peptide clearance receptor, Atrial natriuretic peptide receptor 3, ...
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Disease relevance of NPR3

  • Rat ANP (rANP) mutants that bind rat NPR-A selectively over rat NPR-C were isolated from randomized libraries of rANP-display phage by differential panning [1].
  • We evaluated the associations between a family history of hypertension, cardiovascular phenotype and allelic variants of Npr1 and Npr3, two candidate genes that codify for natriuretic peptide receptors [2].
  • Our results provide evidence that the 37-amino acid cytoplasmic domain of NPR-C is sufficient for signaling inhibition of adenylyl cyclase through a pertussis toxin-sensitive G protein [3].
  • CONCLUSION: In CHF patients, increased local clearance by NPR-C receptors and diminished responsiveness of cardiac GC-A might impair the local antihypertrophic effects of natriuretic peptides and contribute to the progression of cardiac hypertrophy and insufficiency [4].
  • Reversal of cardiomyocyte hypertrophy during LVAD support was accompanied by normalization of ANP, BNP and NPR-C mRNA levels and a significant recovery of GC-A responsiveness to ANP [4].

High impact information on NPR3

  • PKA and PKG, which mediate relaxation, act upstream to desensitize the receptors (VPAC(2) and NPR-C), inhibit adenylyl and guanylyl cyclase activities, and stimulate cAMP-specific PDE3 and PDE4 and cGMP-specific PDE5 activities [5].
  • The human ANP-A receptor has a 32 residue signal sequence followed by a 441 residue extracellular domain homologous to the 60 kd ANP-C receptor [6].
  • However, higher concentrations of ANP and CNP, and low concentrations of des-[Gln(18),Ser(19),Gly(20),Leu(21),Gly(22)]-ANP(4-23)-NH(2) (desANP(4-23)) (analog for NPR-C receptor) exerted antiproliferative actions in three of the cell lines [7].
  • Orthologous mutagenesis at position 188 for either rNPR-C or hNPR-C results in a complete reversal of the pharmacology [8].
  • The third receptor, NPR-C, has been reported to function in the metabolic clearance of ligand and in guanylyl cyclase-independent signal transduction [9].

Chemical compound and disease context of NPR3

  • Several hormones such as angiotensin II, ANP and catecholamines, the levels of which are increased in hypertension, downregulate or upregulate ANP-C receptors and ANP-C receptor-mediated inhibition of adenylyl cyclase [10].
  • Finally, we have found that DOCA-induced hypertension does not modify NPR-A or NPR-C expression in rat glomerular membranes [11].
  • Our results indicate that the cAMP production by NPR-C is not altered in DOCA-induced hypertension, since ANP(1-28), CNP(1-22) and C-ANP, which specifically bind to NPR-C, show a similar inhibitory effect on cAMP production stimulated by the physiological agonist histamine in glomeruli from DOCA-treated rats and controls [11].

Biological context of NPR3

  • The natriuretic peptide receptor-C (NPR-C) constitutes greater than 95% of the natriuretic peptide binding sites in vivo [12].
  • The ANPRC gene was assigned to chromosome 5 using human-specific PCR primers identified by screening a human primer panel on parental DNA samples (shotgun primer screening) [13].
  • The amino acid sequence of the human atrial natriuretic peptide clearance receptor (ANP C-receptor) was deduced from the nucleotide sequence of cDNA clones obtained from human placental and kidney cDNA libraries [14].
  • Peptide binding to these enzymes stimulates the synthesis of the intracellular second messenger, cGMP, whereas a third receptor, NPR-C, lacks enzymatic activity and functions primarily as a clearance receptor [15].
  • Upon transfection of this cDNA into mammalian cells, recombinant expression experiments revealed that the human ANP C-receptor has a high affinity for ANP (6 x 10(-9) M), similar to that observed for the receptor in other species [14].

Anatomical context of NPR3


Associations of NPR3 with chemical compounds

  • It inhibits activation and peptide binding to both guanylate receptors natriuretic peptide receptor (NPR)-A and NPR-B, but has no effect on the non-cyclase receptor NPR-C [20].
  • NPR-A and NPR-B are guanylyl cyclase receptors, whereas NPR-C is non-guanylyl cyclase receptor and is coupled to adenylyl cyclase inhibition or phospholipase C activation through inhibitory guanine nucleotide regulatory protein (Gi) [21].
  • It can be suggested that the antihypertensive action of several types of drugs such as angiotensin converting enzyme inhibitors, angiotensin type 1 receptor antagonists and beta2-adrenergic antagonists may partly be attributed to their ability to modulate the expression and function of the ANP-C receptor [10].
  • Paradoxically, ANF acting via the NPR-C receptor also inhibits cytokine activation of the enzyme-inducible nitric oxide synthase via a cyclic GMP-independent mechanism [22].
  • Vasopressin and histamine, both activators of the inositol phosphate/diacylglycerol phosphate pathway in non-pigmented ciliary epithelial cells, inhibited CNP stimulation of guanylate cyclase (NPR-B) and 125I-ANP binding (NPR-C) by 30-38% [23].

Physical interactions of NPR3

  • 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 [24].

Enzymatic interactions of NPR3

  • Significant increases in retracted cell number were induced by ANF and CNP, but not the NPR-C-specific ring-deleted ANF analog, C-ANF(4-23), during a 15-day treatment [25].

Regulatory relationships of NPR3

  • In contrast, (125)I-ANP purified from medium bathing cells expressing NPR-C, a receptor known to internalize natriuretic peptides, was degraded [26].

Other interactions of NPR3

  • NPR-A and NPR-B are membrane-bound guanylyl cyclases, whereas NPR-C is assumed to function as a clearance-type receptor [27].
  • Moreover, all assessed ANP effects seem to be mediated by the NPR-C [28].
  • All three peptides are cleared by natriuretic peptide-C receptor (NPR-C) and degraded by neutral endopeptidase, both of which are widely expressed in kidney, lung, and vascular wall [29].
  • Unlike other G-protein-coupled receptors, NPR-C receptors have a single transmembrane domain and a short cytoplasmic domain of 37 amino acids, which has a structural specificity like those of other single transmembrane domain receptors [21].
  • A structural comparison of these complexes, with the previous structure of the NPR-C/CNP complex, reveals that NPR-C uses a conformationally inflexible surface to bind three different, highly flexible, NP ligands [30].

Analytical, diagnostic and therapeutic context of NPR3

  • 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 [31].
  • METHODS AND RESULTS: Quantitative "real time" RT-PCR demonstrated that the mRNA expression levels of ANP, BNP and the NP-metabolizing NPR-C receptor were both markedly increased in human failing hearts [4].
  • In atherectomy specimens, most neointimal SMCs showed weak positivity for CNP and NPR-A, but NPR-C was strongly expressed in the neointimal SMCs [32].
  • However, only NPR-C protein was detected by Western blot and immunohistochemical analyses [33].
  • Truncation at position 461, which eliminates the residue Cys469 that is involved in disulphide-linked dimerization, produced a soluble and monomeric form of NPR-C, as determined by gel filtration on Superose 12 [34].


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  2. Allelic variants of natriuretic peptide receptor genes are associated with family history of hypertension and cardiovascular phenotype. Pitzalis, M.V., Sarzani, R., Dessì-Fulgheri, P., Iacoviello, M., Forleo, C., Lucarelli, K., Pietrucci, F., Salvi, F., Sorrentino, S., Romito, R., Guida, P., Rappelli, A., Rizzon, P. J. Hypertens. (2003) [Pubmed]
  3. Cytoplasmic domain of natriuretic peptide receptor-C inhibits adenylyl cyclase. Involvement of a pertussis toxin-sensitive G protein. Anand-Srivastava, M.B., Sehl, P.D., Lowe, D.G. J. Biol. Chem. (1996) [Pubmed]
  4. Left ventricular assist device support reverses altered cardiac expression and function of natriuretic peptides and receptors in end-stage heart failure. Kuhn, M., Voss, M., Mitko, D., Stypmann, J., Schmid, C., Kawaguchi, N., Grabellus, F., Baba, H.A. Cardiovasc. Res. (2004) [Pubmed]
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  7. Proliferative actions of natriuretic peptides on neuroblastoma cells. Involvement of guanylyl cyclase and non-guanylyl cyclase pathways. Lelièvre, V., Pineau, N., Hu, Z., Ioffe, Y., Byun, J.Y., Muller, J.M., Waschek, J.A. J. Biol. Chem. (2001) [Pubmed]
  8. A single residue determines the distinct pharmacology of rat and human natriuretic peptide receptor-C. Engel, A.M., Schoenfeld, J.R., Lowe, D.G. J. Biol. Chem. (1994) [Pubmed]
  9. Extracellular domain-IgG fusion proteins for three human natriuretic peptide receptors. Hormone pharmacology and application to solid phase screening of synthetic peptide antisera. Bennett, B.D., Bennett, G.L., Vitangcol, R.V., Jewett, J.R., Burnier, J., Henzel, W., Lowe, D.G. J. Biol. Chem. (1991) [Pubmed]
  10. Atrial natriuretic peptide-C receptor and membrane signalling in hypertension. Anand-Srivastava, M.B. J. Hypertens. (1997) [Pubmed]
  11. 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]
  12. 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]
  13. 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]
  14. Isolation and functional expression of the human atrial natriuretic peptide clearance receptor cDNA. Porter, J.G., Arfsten, A., Fuller, F., Miller, J.A., Gregory, L.C., Lewicki, J.A. Biochem. Biophys. Res. Commun. (1990) [Pubmed]
  15. Phosphorylation-dependent regulation of the guanylyl cyclase-linked natriuretic peptide receptors. Potthast, R., Potter, L.R. Peptides (2005) [Pubmed]
  16. C-type natriuretic peptide: the endothelial component of the natriuretic peptide system. Chen, H.H., Burnett, J.C. J. Cardiovasc. Pharmacol. (1998) [Pubmed]
  17. Receptors for natriuretic peptides in a human cortical collecting duct cell line. Millul, V., Ardaillou, N., Placier, S., Baudouin, B., Ronco, P.M. Kidney Int. (1997) [Pubmed]
  18. The expression of atrial natriuretic peptide in the oviduct and its functions in pig spermatozoa. Zhang, M., Hong, H., Zhou, B., Jin, S., Wang, C., Fu, M., Wang, S., Xia, G. J. Endocrinol. (2006) [Pubmed]
  19. Effects of natriuretic peptides upon hypothalamo-pituitary-adrenocortical system activity and anxiety behaviour. Wiedemann, K., Jahn, H., Kellner, M. Exp. Clin. Endocrinol. Diabetes (2000) [Pubmed]
  20. Allotopic antagonism of the non-peptide atrial natriuretic peptide (ANP) antagonist HS-142-1 on natriuretic peptide receptor NPR-A. Poirier, H., Labrecque, J., Deschênes, J., DeLéan, A. Biochem. J. (2002) [Pubmed]
  21. Natriuretic peptide receptor-C signaling and regulation. Anand-Srivastava, M.B. Peptides (2005) [Pubmed]
  22. Atrial natriuretic factor modulates nitric oxide production: an ANF-C receptor-mediated effect. McLay, J.S., Chatterjee, P.K., Jardine, A.G., Hawksworth, G.M. J. Hypertens. (1995) [Pubmed]
  23. Differential regulation of natriuretic peptide receptors on ciliary body epithelial cells. Crook, R.B., Chang, A.T. Biochem. J. (1997) [Pubmed]
  24. 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]
  25. Atrial natriuretic factor and C-type natriuretic peptide induce retraction of human thyrocytes in monolayer culture via guanylyl cyclase receptors. Sellitti, D.F., Lagranha, C., Perrella, G., Curcio, F., Doi, S.Q. J. Endocrinol. (2002) [Pubmed]
  26. 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]
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  28. Differential sensitivity of human monocytes and macrophages to ANP: a role of intracellular pH on reactive oxygen species production through the phospholipase involvement. Baldini, P.M., De Vito, P., Martino, A., Fraziano, M., Grimaldi, C., Luly, P., Zalfa, F., Colizzi, V. J. Leukoc. Biol. (2003) [Pubmed]
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  30. Structural determinants of natriuretic peptide receptor specificity and degeneracy. He, X.L., Dukkipati, A., Garcia, K.C. J. Mol. Biol. (2006) [Pubmed]
  31. 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]
  32. C-Type natriuretic peptide and natriuretic peptide receptors are expressed by smooth muscle cells in the neointima after percutaneous coronary intervention. Naruko, T., Itoh, A., Haze, K., Ehara, S., Fukushima, H., Sugama, Y., Shirai, N., Ikura, Y., Ohsawa, M., Ueda, M. Atherosclerosis (2005) [Pubmed]
  33. Identification, regulation and anti-proliferative role of the NPR-C receptor in gastric epithelial cells. Gower, W.R., Carter, G.M., McAfee, Q., Solivan, S.M. Mol. Cell. Biochem. (2006) [Pubmed]
  34. Structural analysis of natriuretic peptide receptor-C by truncation and site-directed mutagenesis. Itakura, M., Suzuki, H., Hirose, S. Biochem. J. (1997) [Pubmed]
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