atrial natriuretic factor receptors


Summary: Cell surface proteins that bind ATRIAL NATRIURETIC FACTOR with high affinity and trigger intracellular changes influencing the behavior of cells. They contain intrinsic guanylyl cyclase activity.

Top Publications

  1. Knowles J, Esposito G, Mao L, Hagaman J, Fox J, Smithies O, et al. Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice. J Clin Invest. 2001;107:975-84 pubmed
    ..Taken together, these results suggest that the NPRA system has direct antihypertrophic actions in the heart, independent of its role in BP control. ..
  2. Rubattu S, Stanzione R, Di Angelantonio E, Zanda B, Evangelista A, Tarasi D, et al. Atrial natriuretic peptide gene polymorphisms and risk of ischemic stroke in humans. Stroke. 2004;35:814-8 pubmed
    ..5-fold increased risk of stroke (95% confidence interval, 1.5 to 19.4). Our findings support a direct contributory role of ANP to stroke in humans. A significant interaction between ANP and NPRA on stroke occurrence was found. ..
  3. Fan D, Bryan P, Antos L, Potthast R, Potter L. 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. Mol Pharmacol. 2005;67:174-83 pubmed
    ..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. ..
  4. Tsuji T, Kunieda T. A loss-of-function mutation in natriuretic peptide receptor 2 (Npr2) gene is responsible for disproportionate dwarfism in cn/cn mouse. J Biol Chem. 2005;280:14288-92 pubmed
  5. Muller D, Cortes Dericks L, Budnik L, Brunswig Spickenheier B, Pancratius M, Speth R, et al. Homologous and lysophosphatidic acid-induced desensitization of the atrial natriuretic peptide receptor, guanylyl cyclase-A, in MA-10 leydig cells. Endocrinology. 2006;147:2974-85 pubmed
    ..The morphoregulatory activities exerted by LPA suggest a crucial role for Leydig cell physiology. ..
  6. Schulz S. C-type natriuretic peptide and guanylyl cyclase B receptor. Peptides. 2005;26:1024-34 pubmed
    ..This review will examine the structure and function of GC-B, and summarize the physiological processes in which this receptor is thought to participate. ..
  7. Stubbe H, Traber D, Booke M, Traber L, Westphal M, Van Aken H, et al. Role of atrial natriuretic peptide in pulmonary permeability and vasoregulation in ovine sepsis. Crit Care Med. 2004;32:2491-5 pubmed
    ..Atrial natriuretic peptide may therefore play a protective role for the alveolar-capillary barrier during sepsis. ..
  8. Tamura N, Doolittle L, Hammer R, Shelton J, Richardson J, Garbers D. Critical roles of the guanylyl cyclase B receptor in endochondral ossification and development of female reproductive organs. Proc Natl Acad Sci U S A. 2004;101:17300-5 pubmed
    ..This result was due to the failure of the female reproductive tract to develop. Thus, the guanylyl cyclase B receptor is critical for the development of both bone and female reproductive organs. ..
  9. Rollin R, Mediero A, Roldán Pallarès M, Fernandez Cruz A, Fernández Durango R. Natriuretic peptide system in the human retina. Mol Vis. 2004;10:15-22 pubmed
    ..The expression of NPs in neural retinal, glial, and vascular elements of the normal adult retina suggests a role for these peptides in maintaining both the neural and vascular integrity of the mature retina. ..

More Information


  1. Kuhn M. Molecular physiology of natriuretic peptide signalling. Basic Res Cardiol. 2004;99:76-82 pubmed
  2. Rahmutula D, Gardner D. C-type natriuretic Peptide down-regulates expression of its cognate receptor in rat aortic smooth muscle cells. Endocrinology. 2005;146:4968-74 pubmed
    ..This report provides the first documentation that CNP is capable of autoregulating the expression of its cognate receptor. ..
  3. Madhani M, Scotland R, MacAllister R, Hobbs A. Vascular natriuretic peptide receptor-linked particulate guanylate cyclases are modulated by nitric oxide-cyclic GMP signalling. Br J Pharmacol. 2003;139:1289-96 pubmed
  4. Nakayama T, Soma M, Mizutani Y, Xinjuan X, Honye J, Kaneko Y, et al. A novel missense mutation of exon 3 in the type A human natriuretic peptide receptor gene: possible association with essential hypertension. Hypertens Res. 2002;25:395-401 pubmed
    ..We conclude that the significance of homozygous M3411 mutation in exon 3 is worth investigating for its possible association with EH. ..
  5. He Xl -, Chow Dc -, Martick M, Garcia K. Allosteric activation of a spring-loaded natriuretic peptide receptor dimer by hormone. Science. 2001;293:1657-62 pubmed
    ..In each monomer, the opening of an interdomain cleft, which is tethered together by a linker peptide acting as a molecular spring, is likely a conserved allosteric trigger for intracellular signaling by the natriuretic receptor family. ..
  6. Moro C, Crampes F, Sengenes C, De Glisezinski I, Galitzky J, Thalamas C, et al. Atrial natriuretic peptide contributes to physiological control of lipid mobilization in humans. FASEB J. 2004;18:908-10 pubmed
    ..Oral beta-adrenergic receptor blockade, which potentiates exercise-induced ANP release by the heart, may contribute to lipid mobilization in SCAT. The potential relevance of an ANP-related lipid-mobilizing pathway is discussed. ..
  7. Kaneki H, Kurokawa M, Ide H. The receptor attributable to C-type natriuretic peptide-induced differentiation of osteoblasts is switched from type B- to type C-natriuretic peptide receptor with aging. J Cell Biochem. 2008;103:753-64 pubmed
    ..From these results, we concluded that CNP acts as a positive regulator of bone formation by osteoblasts and that the signaling pathway for CNP is switched from NPR-B/cGMP/PKG to NPR-C/G(i) protein/PLC with aging. ..
  8. Ogawa H, Qiu Y, Ogata C, Misono K. Crystal structure of hormone-bound atrial natriuretic peptide receptor extracellular domain: rotation mechanism for transmembrane signal transduction. J Biol Chem. 2004;279:28625-31 pubmed
    ..These results suggest that transmembrane signaling by the ANP receptor is initiated via a hormone-induced rotation mechanism. ..
  9. Madhani M, Okorie M, Hobbs A, MacAllister R. Reciprocal regulation of human soluble and particulate guanylate cyclases in vivo. Br J Pharmacol. 2006;149:797-801 pubmed
    ..These findings have implications for understanding the link between natriuretic peptide activity and cardiovascular risk. ..
  10. Parat M, McNicoll N, Wilkes B, Fournier A, De Léan A. Role of extracellular domain dimerization in agonist-induced activation of natriuretic peptide receptor A. Mol Pharmacol. 2008;73:431-40 pubmed
    ..Furthermore, the highly sensitive fluorescence assay designed to assess dimerization could serve as a powerful tool for further detailing the kinetic steps involved in natriuretic peptide receptor binding and activation. ..
  11. Dicicco Bloom E, Lelievre V, Zhou X, Rodriguez W, Tam J, Waschek J. Embryonic expression and multifunctional actions of the natriuretic peptides and receptors in the developing nervous system. Dev Biol. 2004;271:161-75 pubmed
  12. D Souza S, Davis M, Baxter G. Autocrine and paracrine actions of natriuretic peptides in the heart. Pharmacol Ther. 2004;101:113-29 pubmed
    ..Ultimately, insights from the autocrine/paracrine actions of natriuretic peptides may provide routes to therapeutic application in cardiac diseases of natriuretic peptides and drugs that modify their availability. ..
  13. Kilic A, Velic A, De Windt L, Fabritz L, Voss M, Mitko D, et al. Enhanced activity of the myocardial Na+/H+ exchanger NHE-1 contributes to cardiac remodeling in atrial natriuretic peptide receptor-deficient mice. Circulation. 2005;112:2307-17 pubmed
  14. Sabrane K, Gambaryan S, Brandes R, Holtwick R, Voss M, Kuhn M. Increased sensitivity to endothelial nitric oxide (NO) contributes to arterial normotension in mice with vascular smooth muscle-selective deletion of the atrial natriuretic peptide (ANP) receptor. J Biol Chem. 2003;278:17963-8 pubmed
    ..Increased vasodilating responsiveness to endothelial NO contributes to compensate for the missing vasodilating effect of ANP in SMC GC-A KO mice. ..
  15. Holtwick R, van Eickels M, Skryabin B, Baba H, Bubikat A, Begrow F, et al. Pressure-independent cardiac hypertrophy in mice with cardiomyocyte-restricted inactivation of the atrial natriuretic peptide receptor guanylyl cyclase-A. J Clin Invest. 2003;111:1399-407 pubmed
    ..This phenotype is consistent with a local function of the ANP/GC-A system to moderate the molecular program of cardiac hypertrophy. ..
  16. Sabbatini M. Natriuretic peptides as regulatory mediators of secretory activity in the digestive system. Regul Pept. 2009;154:5-15 pubmed publisher
    ..Overall, these findings indicate that ANP and CNP are members of the large group of regulatory peptides affecting digestive secretions...
  17. Bartels C, Bukulmez H, Padayatti P, Rhee D, van Ravenswaaij Arts C, Pauli R, et al. Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. Am J Hum Genet. 2004;75:27-34 pubmed
    ..We conclude that, although NPR-B is expressed in a number of tissues, its major role is in the regulation of skeletal growth. ..
  18. Nakayama T, Soma M, Saito S, Honye J, Sato M, Aoi N, et al. Missense mutation of exon 3 in the type A human natriuretic peptide receptor gene is associated with myocardial infarction. Med Sci Monit. 2003;9:CR505-10 pubmed
    ..028). The C allele was found more frequently in the MI group than in the control group. We conclude that the M341I missense mutation is associated with risk for MI and may be a genetic marker of MI in Japanese people. ..
  19. Kuhn M. Structure, regulation, and function of mammalian membrane guanylyl cyclase receptors, with a focus on guanylyl cyclase-A. Circ Res. 2003;93:700-9 pubmed
  20. Morita R, Ukyo N, Furuya M, Uchiyama T, Hori T. Atrial natriuretic peptide polarizes human dendritic cells toward a Th2-promoting phenotype through its receptor guanylyl cyclase-coupled receptor A. J Immunol. 2003;170:5869-75 pubmed
    ..These results indicate that ANP polarizes human DCs toward a Th2-promoting phenotype through GC-A and thus can regulate immune responses. ..
  21. Li Y, Kishimoto I, Saito Y, Harada M, Kuwahara K, Izumi T, et al. Guanylyl cyclase-A inhibits angiotensin II type 1A receptor-mediated cardiac remodeling, an endogenous protective mechanism in the heart. Circulation. 2002;106:1722-8 pubmed
    ..These results suggest that cardiac hypertrophy and fibrosis of GC-A-deficient mice are partially ascribed to an augmented cardiac AT1A signaling and that GC-A inhibits AT1A signaling-mediated excessive remodeling. ..
  22. Yu Y, Cao L, Yang X. Modulation by brain natriuretic peptide of GABA receptors on rat retinal ON-type bipolar cells. J Neurosci. 2006;26:696-707 pubmed
    ..We therefore conclude that the increased calcium release from ryanodine-sensitive calcium stores by BNP may be responsible for the BNP-caused GABAA response suppression in ON-type BCs through stimulating calmodulin. ..
  23. Fortin Y, De Léan A. Role of cyclic GMP and calcineurin in homologous and heterologous desensitization of natriuretic peptide receptor-A. Can J Physiol Pharmacol. 2006;84:539-46 pubmed
    ..Our results also indicate for the first time a role for calcineurin in NPR-A heterologous desensitization...
  24. Kong X, Wang X, Xu W, Behera S, Hellermann G, Kumar A, et al. Natriuretic peptide receptor a as a novel anticancer target. Cancer Res. 2008;68:249-56 pubmed publisher
    ..These results suggest that NPRA is involved in tumor angiogenesis and represents a new target for cancer therapy. ..
  25. Kumar P, Bolden G, Arise K, Krazit S, Pandey K. Regulation of natriuretic peptide receptor-A gene expression and stimulation of its guanylate cyclase activity by transcription factor Ets-1. Biosci Rep. 2009;29:57-70 pubmed publisher
    ..Collectively, the present study demonstrates that Npr1 gene transcription and GC activity of the receptor are critically controlled by Ets-1 in target cells. ..
  26. Hartmann M, Skryabin B, Muller T, Gazinski A, Schröter J, Gassner B, et al. Alternative splicing of the guanylyl cyclase-A receptor modulates atrial natriuretic peptide signaling. J Biol Chem. 2008;283:28313-20 pubmed publisher
    ..We conclude that alternative splicing can regulate endogenous ANP/GC-A signaling. Angiotensin II-induced alternative splicing of GC-A may represent a novel mechanism for reducing the sensitivity to ANP. ..
  27. Ogawa H, Qiu Y, Huang L, Tam Chang S, Young H, Misono K. Structure of the atrial natriuretic peptide receptor extracellular domain in the unbound and hormone-bound states by single-particle electron microscopy. FEBS J. 2009;276:1347-55 pubmed publisher
    ..The results also support the proposed rotation mechanism for transmembrane signaling by the ANP receptor. ..
  28. Zhong L, Chu E, Chu J, Chu T. CNP-induced changes in pHi, cGMP/cAMP and mRNA expression of natriuretic peptide receptors in human trabecular meshwork cells. J Ocul Pharmacol Ther. 2003;19:425-36 pubmed
    ..CNP activates NPR-B receptors preferentially to increase cGMP accumulation and acts through the PTX-sensitive cAMP-signaling pathway leading to a decrease in pH(i). ..
  29. Bryan P, Potter L. The atrial natriuretic peptide receptor (NPR-A/GC-A) is dephosphorylated by distinct microcystin-sensitive and magnesium-dependent protein phosphatases. J Biol Chem. 2002;277:16041-7 pubmed
    ..Finally, we observed that the desensitization of NPR-A in membranes from mouse kidneys and NIH3T3 cells was increased by prior exposure to atrial natriuretic peptide, suggesting that hormone binding enhances receptor dephosphorylation. ..
  30. Pattanaik P, Fromondi L, Ng K, He J, van den Akker F. Expression, purification, and characterization of the intra-cellular domain of the ANP receptor. Biochimie. 2009;91:888-93 pubmed publisher
    ..These receptor insights could aid in the development of novel therapeutics as the GCA receptor is a key drug target for cardiovascular diseases. ..
  31. Oliver P, Fox J, Kim R, Rockman H, Kim H, Reddick R, et al. Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A. Proc Natl Acad Sci U S A. 1997;94:14730-5 pubmed
    ..Thus complete absence of NPRA causes hypertension in mice and leads to cardiac hypertrophy and, particularly in males, lethal vascular events similar to those seen in untreated human hypertensive patients. ..
  32. Suga S, Nakao K, Hosoda K, Mukoyama M, Ogawa Y, Shirakami G, et al. Receptor selectivity of natriuretic peptide family, atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide. Endocrinology. 1992;130:229-39 pubmed
    ..These findings on the receptor selectivity of the natriuretic peptide family provide a new insight into the understanding of the physiological and clinical implications of the natriuretic peptide system. ..
  33. Levin E, Frank H. Natriuretic peptides inhibit rat astroglial proliferation: mediation by C receptor. Am J Physiol. 1991;261:R453-7 pubmed
    ..The inhibitory effects are not the result of inhibiting the proliferative effects of an endogenous growth factor and are cAMP independent...
  34. Chinkers M, Garbers D, Chang M, Lowe D, Chin H, Goeddel D, et al. A membrane form of guanylate cyclase is an atrial natriuretic peptide receptor. Nature. 1989;338:78-83 pubmed
    ..The ANP receptor/guanylate cyclase represents a new class of mammalian cell-surface receptors which contain an extracellular ligand-binding domain and an intracellular guanylate cyclase catalytic domain. ..
  35. Schulz S, Singh S, Bellet R, Singh G, Tubb D, Chin H, et al. The primary structure of a plasma membrane guanylate cyclase demonstrates diversity within this new receptor family. Cell. 1989;58:1155-62 pubmed
  36. Lopez M, Wong S, Kishimoto I, Dubois S, Mach V, Friesen J, et al. Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide. Nature. 1995;378:65-8 pubmed
  37. Silberbach M, Roberts C. Natriuretic peptide signalling: molecular and cellular pathways to growth regulation. Cell Signal. 2001;13:221-31 pubmed
    ..The inhibition of cardiac growth and hypertrophy may be an important but underappreciated action of the NP signalling system. ..
  38. Pedram A, Razandi M, Levin E. Natriuretic peptides suppress vascular endothelial cell growth factor signaling to angiogenesis. Endocrinology. 2001;142:1578-86 pubmed
    ..The actions are significantly prevented by NP, which act through both the NPRC and GC receptors to block growth factor signaling. Thus, NP are candidate antiangiogenesis factors that inhibit both the synthesis and function of VEGF. ..
  39. Potter L, Hunter T. Phosphorylation of the kinase homology domain is essential for activation of the A-type natriuretic peptide receptor. Mol Cell Biol. 1998;18:2164-72 pubmed
    ..We conclude that phosphorylation of the KHD is absolutely required for hormone-dependent activation of NPR-A. ..
  40. Matsukawa N, Grzesik W, Takahashi N, Pandey K, Pang S, Yamauchi M, et al. The natriuretic peptide clearance receptor locally modulates the physiological effects of the natriuretic peptide system. Proc Natl Acad Sci U S A. 1999;96:7403-8 pubmed
    ..We conclude that NPRC modulates the availability of the natriuretic peptides at their target organs, thereby allowing the activity of the natriuretic peptide system to be tailored to specific local needs. ..
  41. Jaubert J, Jaubert F, Martin N, Washburn L, Lee B, Eicher E, et al. Three new allelic mouse mutations that cause skeletal overgrowth involve the natriuretic peptide receptor C gene (Npr3). Proc Natl Acad Sci U S A. 1999;96:10278-83 pubmed
  42. Potter L, Hunter T. Identification and characterization of the phosphorylation sites of the guanylyl cyclase-linked natriuretic peptide receptors A and B. Methods. 1999;19:506-20 pubmed
    ..In this review, we give a detailed description of the phosphopeptide mapping techniques that were used to identify and characterize these sites and discuss the potential pitfalls that are associated with them. ..
  43. Yasoda A, Nakao K. [Hormones and osteoporosis update. Effects of natriuretic peptides on endochondral bone growth]. Clin Calcium. 2009;19:1003-8 pubmed publisher
    ..Moreover, we will have to translate this effect of the CNP/GC-B system on endochondral bone growth into skeletal dysplasias. ..
  44. Wu Wong J. Vitamin D receptor: a highly versatile nuclear receptor. Kidney Int. 2007;72:237-9 pubmed that VDR is involved in regulating type A natriuretic peptide receptor (NPR-A) in inner medullary collecting duct cells. The regulation of NPR-A may be one of several mechanisms by which VDR activation reduces CVD risk in CKD. ..
  45. Yu J, Zhu M, Fu Z, Zhu X, Zhao Y, Chen B. Vasorelaxing action of vasonatrin peptide is associated with activation of large-conductance Ca(2+)-activated potassium channels in vascular smooth muscle cells. Physiol Res. 2010;59:187-94 pubmed
    ..Taken together, VNP acts as a potent vasodilator, and NPRA/B-cGMP-BK(Ca) is one possible signaling system involved in VNP induced relaxation. ..
  46. Tsukada T, Nobata S, Hyodo S, Takei Y. Area postrema, a brain circumventricular organ, is the site of antidipsogenic action of circulating atrial natriuretic peptide in eels. J Exp Biol. 2007;210:3970-8 pubmed
    ..These results strongly suggest that the AP, a circumventricular organ without a blood-brain barrier, serves as a functional window of access for the circulating ANP to inhibit drinking in eels. ..
  47. Baldini P, De Vito P, Vismara D, Bagni C, Zalfa F, Minieri M, et al. Atrial natriuretic peptide effects on intracellular pH changes and ROS production in HEPG2 cells: role of p38 MAPK and phospholipase D. Cell Physiol Biochem. 2005;15:77-88 pubmed
    ..Our results indicate that ANP recruits a signal pathway associated with p38 MAPK, NHE-1 and PLD responsible for ROS production, suggesting a possible role for ANP as novel modulator of ROS generation in HepG2 cells. ..
  48. Zielinska M, Fresko I, Konopacka A, Felipo V, Albrecht J. Hyperammonemia inhibits the natriuretic peptide receptor 2 (NPR-2)-mediated cyclic GMP synthesis in the astrocytic compartment of rat cerebral cortex slices. Neurotoxicology. 2007;28:1260-3 pubmed
    ..Deregulation of NPR-2 function in astrocytes by ammonia may contribute to neurophysiological symptoms of HA. ..
  49. Langenickel T, Buttgereit J, Pagel Langenickel I, Lindner M, Monti J, Beuerlein K, et al. Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B. Proc Natl Acad Sci U S A. 2006;103:4735-40 pubmed
    ..The hypertrophic phenotype is further enhanced in chronic volume overload-induced congestive heart failure. Thus, this study provides evidence linking NPR-B signaling to the control of cardiac growth. ..
  50. Medvede A, Abakumova OYu -, Podobed O, Tsvetkova T, Sandler M, Glover V. Effects of isatin on atrial natriuretic peptide-mediated accumulation of cGMP and guanylyl cyclase activity of PC12 cells. Life Sci. 2001;69:1783-90 pubmed
    ..5% ECS. The data obtained suggest that, in intact cells, the manifestation of the isatin effect on ANP-mediated signal transduction may depend on intracellular factor(s), possibly interacting at the kinase domain. ..
  51. Holtwick R, Gotthardt M, Skryabin B, Steinmetz M, Potthast R, Zetsche B, et al. Smooth muscle-selective deletion of guanylyl cyclase-A prevents the acute but not chronic effects of ANP on blood pressure. Proc Natl Acad Sci U S A. 2002;99:7142-7 pubmed
    ..We conclude that vascular GC-A is dispensable in the chronic and critical in the acute moderation of arterial blood pressure by ANP. ..
  52. Zhao L, Mason N, Strange J, Walker H, Wilkins M. Beneficial effects of phosphodiesterase 5 inhibition in pulmonary hypertension are influenced by natriuretic Peptide activity. Circulation. 2003;107:234-7 pubmed
    ..The natriuretic peptide pathway influences the response to PDE5 inhibition in hypoxia-induced pulmonary hypertension, particularly its effects on RV hypertrophy and vascular remodeling. ..
  53. Li Y, Kishimoto I, Saito Y, Harada M, Kuwahara K, Izumi T, et al. Androgen contributes to gender-related cardiac hypertrophy and fibrosis in mice lacking the gene encoding guanylyl cyclase-A. Endocrinology. 2004;145:951-8 pubmed
    ..Thus, we suggest that androgens contribute to gender-related differences in cardiac hypertrophy and fibrosis by a mechanism involving AT1A receptors and GC-A. ..