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Matsukawa, N. et al. The natriuretic peptide clearance receptor locally modulates the physiological effects of the natriuretic peptide system. Proc. Natl. Acad. Sci. USA 96, 7403-7408

Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599-7525, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/1999; 96(13). DOI: 10.1073/pnas.96.13.7403
Source: PubMed

ABSTRACT

Natriuretic peptides (NPs), mainly produced in heart [atrial (ANP) and B-type (BNP)], brain (CNP), and kidney (urodilatin), decrease blood pressure and increase salt excretion. These functions are mediated by natriuretic peptide receptors A and B (NPRA and NPRB) having cytoplasmic guanylyl cyclase domains that are stimulated when the receptors bind ligand. A more abundantly expressed receptor (NPRC or C-type) has a short cytoplasmic domain without guanylyl cyclase activity. NPRC is thought to act as a clearance receptor, although it may have additional functions. To test how NPRC affects the cardiovascular and renal systems, we inactivated its gene (Npr3) in mice by homologous recombination. The half life of [125I]ANP in the circulation of homozygotes lacking NPRC is two-thirds longer than in the wild type, although plasma levels of ANP and BNP in heterozygotes and homozygotes are close to the wild type. Heterozygotes and homozygotes have a progressively reduced ability to concentrate urine, exhibit mild diuresis, and tend to be blood volume depleted. Blood pressure in the homozygotes is 8 mmHg (1 mmHg = 133 Pa) below normal. These results are consistent with the sole cardiovascular/renal function of NPRC being to clear natriuretic peptides, thereby modulating local effects of the natriuretic peptide system. Unexpectedly, Npr3 -/- homozygotes have skeletal deformities associated with a considerable increase in bone turnover. The phenotype is consistent with the bone function of NPRC being to clear locally synthesized CNP and modulate its effects. 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

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Available from: Stephen C Pang, May 13, 2014
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    • "NPRC is important in the maintenance of BP and extracellular fluid volume. NPRC knockout mice show reduced clearance of circulating natriuretic peptides and have lower BP (Matsukawa et al., 1999). There have been many studies on the NPRA and NPRC genes and hypertension. "

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    • "However, three potential signals for N-glycosylation and several serine and threonine for O-linked glycosylation sites are known to be present in the extracellular domain of NPRC (Fuller et al., 1988). Previously, it has been suggested that NPRC may function as a clearance receptor to remove and clear NPs from the circulation, however, a number of studies have provided the evidence that NPRC plays roles in the biological actions of NPs (Anand-Srivastava and Trachte, 1993; Matsukawa et al., 1999; Zhou and Murthy, 2003). Thus, it is evident that the clearance name carries only by a default nomenclature to NPRC. "
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    ABSTRACT: Thus far, three related natriuretic peptides (NPs) and three distinct sub-types of cognate NP receptors have been identified and characterized based on the specific ligand binding affinities, guanylyl cyclase activity, and generation of intracellular cGMP. Atrial and brain natriuretic peptides (ANP and BNP) specifically bind and activate guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA), and C-type natriuretic peptide (CNP) shows specificity to activate guanylyl cyclase/natriuretic peptide receptor-B (GC-B/NPRB). All three NPs bind to natriuretic peptide receptor-C (NPRC), which is also known as clearance or silent receptor. The NPRA is considered the principal biologically active receptor of NP family; however, the molecular signaling mechanisms of NP receptors are not well understood. The activation of NPRA and NPRB produces the intracellular second messenger cGMP, which serves as the major signaling molecule of all three NPs. The activation of NPRB in response to CNP also produces the intracellular cGMP; however, at lower magnitude than that of NPRA, which is activated by ANP and BNP. In addition to enhanced accumulation of intracellular cGMP in response to all three NPs, the levels of cAMP, Ca(2+) and inositol triphosphate (IP3) have also been reported to be altered in different cells and tissue types. Interestingly, ANP has been found to lower the concentrations of cAMP, Ca(2+), and IP3; however, NPRC has been proposed to increase the levels of these metabolic signaling molecules. The mechanistic studies of decreased and/or increased levels of cAMP, Ca(2+), and IP3 in response to NPs and their receptors have not yet been clearly established. This review focuses on the signaling mechanisms of ANP/NPRA and their biological effects involving an increased level of intracellular accumulation of cGMP and a decreased level of cAMP, Ca(2+), and IP3 in different cells and tissue systems.
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    • "The second class of NP receptors is termed NPRB and conversely preferentially binds to CNP, but with lesser affinity to ANP and BNP. The third, NPRC is an interesting receptor as its role is to clear circulating NPs, especially ANP (Anand-Srivastava, 2005) thereby in this unique manner controlling NP interactions with its receptors at its site of action (Matsukawa et al., 1999). "
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