Alternative titles; symbols
HGNC Approved Gene Symbol: NPR1
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38): 1:153,678,688-153,693,992 (from NCBI)
Guanylyl cyclases, catalyzing the production of cGMP from GTP, are classified as soluble and membrane forms (Garbers and Lowe, 1994). 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; 108961). Also see NPR3 (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 (108780) and BNP (600295), respectively).
Lowe et al. (1989) cloned cDNAs encoding the 115-kD ANP receptor A. The protein has a 32-residue signal sequence followed by a 441-residue extracellular domain homologous to the ANPC (108962). A 21-residue transmembrane domain precedes a 568-residue cytoplasmic domain with homology to the protein kinase family and to a subunit of the soluble guanylate cyclase.
The precursor of ANP is produced and stored mainly in the right atrium of the heart (see Oliver et al., 1997). ANP formed from this precursor is released in response to atrial stretch. Once in the circulation, ANP binds to NPR1, also known as guanylate cyclase A, mainly in the kidney, vascular tissue, and adrenal gland. This binding induces an increase in intracellular cGMP and initiates natriuresis, diuresis, and vasodilation, all of which contribute to lowering blood pressure. BNP, a structurally related peptide formed mainly in the cardiac ventricles, also acts through NPR1 and has effects similar to ANP.
Several studies have suggested a relationship between ANP and blood pressure. For example, the plasma ANP levels in children of 2 normotensive parents are higher than in children of 1 normotensive and 1 hypertensive parent, especially at high levels of salt intake (Ferrari et al., 1990).
Lowe et al. (1990) assigned the ANPRA gene to 1q21-qter by PCR analysis of genomic DNA from somatic cell hybrids. By in situ hybridization, they refined the localization to 1q21-q22.
To determine whether there are common quantitative variants in NPR1, Knowles et al. (2003) sequenced the entire gene and identified 10 polymorphic sites in its noncoding sequence by using DNA from 34 unrelated individuals. Transient expression analysis in cultured cells of reporter plasmids with the proximal promoter sequence of NPR1 and its 3-prime untranslated regions showed that these polymorphisms have functional effects. Knowles et al. (2003) concluded that common NPR1 alleles can alter expression of the gene as much as 2-fold, and could therefore significantly affect genetic risks for essential hypertension (145500) and cardiac hypertrophy.
To study the role of NPRA in the regulation of blood pressure and in the cardiovascular response to sustained hypertension, Oliver et al. (1997) generated mice completely lacking this receptor. They found that mice lacking a functional Npr1 gene coding for NPRA had elevated blood pressures and heart exhibiting marked hypertrophy with interstitial fibrosis resembling that seen in human hypertensive heart disease. Echocardiographic evaluation of the mice demonstrated a compensated state of systemic hypertension in which cardiac hypertrophy and dilatation were evident but with no reduction in ventricular performance. Nevertheless, sudden death, with morphologic evidence indicative in some animals of congestive heart failure and in others of aortic dissection, occurred in all 15 male mice lacking Npr1 before 6 months of age, and in 1 of 16 females in this study.
Oliver et al. (1998) generated mice with 1, 2, 3, or 4 copies of the Npr1 gene to determine whether differences in Npr1 expression affect blood pressure (BP). Atrial natriuretic peptide-dependent guanylate cyclase activity ranged from one-half normal in 1-copy mice to twice normal in 4-copy mice. Copy number had no effect on hematocrit, body weight, or the weights of kidney, lung, and heart. It also had no effect on the histologic appearance of kidney, lung, and heart. On diets with different concentrations of salt, 1-copy males had higher BP than wildtype, 2-copy males, while 3-copy males had a lower BP. BP was significantly higher in 1-copy males on a high-salt diet than a low-salt diet, whereas BP was significantly lower in 4-copy males on the high-salt diet than on the low-salt diet. Oliver et al. (1998) concluded that low Npr1 expression leads to a salt-sensitive increase in BP, whereas high Npr1 expression lowers BP and protects against high dietary salt.
Although mice deficient in GC-A display an elevated blood pressure, the resultant cardiac hypertrophy is much greater than in other mouse models of hypertension. Kishimoto et al. (2001) overproduced GC-A in the cardiac myocytes of wildtype or GC-A-null animals. Introduction of the GC-A transgene did not alter blood pressure or heart rate as a function of genotype. Cardiac myocyte size was larger (approximately 20%) in GC-A-null than in wildtype animals. However, introduction of the GC-A transgene reduced cardiac myocyte size in both wildtype and null mice. Coincident with the reduction in myocyte size, both ANP mRNA and ANP content were significantly reduced by overexpression of GC-A, and this reduction was independent of genotype. This genetic model, therefore, separated a regulation of cardiac myocyte size by blood pressure from local regulation by a GC-mediated pathway.
Ferrari, P., Weidmann, P., Ferrier, C., Dietler, R., Hollmann, R., Piso, R. J., Wey, J., Shaw, S. Dysregulation of atrial natriuretic factor in hypertension-prone man. J. Clin. Endocr. Metab. 71: 944-951, 1990. [PubMed: 2144858] [Full Text: https://doi.org/10.1210/jcem-71-4-944]
Garbers, D. L., Lowe, D. G. Guanylyl cyclase receptors. J. Biol. Chem. 269: 30741-30744, 1994. [PubMed: 7982997]
Kishimoto, I., Rossi, K., Garbers, D. L. A genetic model provides evidence that the receptor for atrial natriuretic peptide (guanylyl cyclase-A) inhibits cardiac ventricular myocyte hypertrophy. Proc. Nat. Acad. Sci. 98: 2703-2706, 2001. [PubMed: 11226303] [Full Text: https://doi.org/10.1073/pnas.051625598]
Knowles, J. W., Erickson, L. M., Guy, V. K., Sigel, C. S., Wilder, J. C., Maeda, N. Common variations in noncoding regions of the human natriuretic peptide receptor A gene have quantitative effects. Hum. Genet. 112: 62-70, 2003. [PubMed: 12483301] [Full Text: https://doi.org/10.1007/s00439-002-0834-z]
Lowe, D. G., Chang, M. S., Hellmiss, R., Chen, E., Singh, S., Garbers, D. L., Goeddel, D. V. Human atrial natriuretic peptide receptor defines a new paradigm for second messenger signal transduction. EMBO J. 8: 1377-1384, 1989. [PubMed: 2569967] [Full Text: https://doi.org/10.1002/j.1460-2075.1989.tb03518.x]
Lowe, D. G., Klisak, I., Sparkes, R. S., Mohandas, T., Goeddel, D. V. Chromosomal distribution of three members of the human natriuretic peptide receptor/guanylyl cyclase gene family. Genomics 8: 304-312, 1990. [PubMed: 1979052] [Full Text: https://doi.org/10.1016/0888-7543(90)90286-4]
Oliver, P. M., Fox, J. E., Kim, R., Rockman, H. A., Kim, H.-S., Reddick, R. L., Pandey, K. N., Milgram, S. L., Smithies, O., Maeda, N. Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A. Proc. Nat. Acad. Sci. 94: 14730-14735, 1997. [PubMed: 9405681] [Full Text: https://doi.org/10.1073/pnas.94.26.14730]
Oliver, P. M., John, S. W. M., Purdy, K. E., Kim, R., Maeda, N., Goy, M. F., Smithies, O. Natriuretic peptide receptor 1 expression influences blood pressures of mice in a dose-dependent manner. Proc. Nat. Acad. Sci. 95: 2547-2551, 1998. [PubMed: 9482923] [Full Text: https://doi.org/10.1073/pnas.95.5.2547]