Disease relevance of NPR2

• 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 [1].
• In this experiment, we studied this I/D polymorphism in the NPRB gene in 241 subjects, including 118 patients with cerebral infarction (the CI group) and 123 control subjects (the non-CI group) [2].
• In the present study, our objectives are to identify the polymorphisms of the NPRB gene and investigate the association of this gene with essential hypertension (EH) [3].

High impact information on NPR2

• Recently, gene deletion revealed a predominant role of NPR-B in endochondral ossification and development of female reproductive organs [4].
• We sequenced DNA from 21 families affected by AMDM and found 4 nonsense mutations, 4 frameshift mutations, 2 splice-site mutations, and 11 missense mutations [5].
• Some experiments indicate that ANP and BNP may act synergistically, especially during cardiac stress; however, the high level of structural diversity of BNP among species and the ability of porcine BNP, but not human BNP, to activate human NPR-B suggest that an as yet unidentified receptor may exist that specifically recognizes BNP [6].
• Of the three known NPRs, two, NPR-A and NPR-B, are capable of synthesizing their own second messenger, cGMP [6].
• Multiple logistic linear regression analysis indicated that the NPR-B genotype is associated significantly with EH (odds ratio 1.55; 95% confidence interval, 1.02 to 2.35) [7].

Biological context of NPR2

• 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 [8].
• Natriuretic peptide receptor A (NPR-A/GC-A) and B (NPR-B/GC-B) are members of the transmembrane guanylyl cyclase family that mediate the effects of natriuretic peptides via the second messenger, cGMP [8].
• Cleavable biotinylation and noncleavable biotinylation assays indicated that neither NPR-A nor NPR-B was internalized or degraded in response to natriuretic peptide binding [8].
• Using 5' rapid amplification of cDNA ends analysis, we have identified the 5' terminus of the hNPR-B gene transcript approximately 732 base pairs upstream from the presumed translation start site of the protein [9].
• Site-directed mutagenesis of the proximal promoter revealed a series of GC-rich sequences, 5 of which contributed modestly (approximately 25%) to basal hNPR-B promoter activity [9].

Anatomical context of NPR2

• The type B natriuretic peptide receptor (NPR-B) is the cognate receptor for the C-type natriuretic peptide and, as such, is responsible for signaling growth-suppressant activity in vascular smooth muscle cells [9].
• Monoclonal antibodies (mAbs) against human natriuretic peptide receptor-A (NPR-A) or NPR-B were produced using NPR-expressing Chinese hamster ovary (CHO) cells and soluble chimeric NPRs consisting of the extracellular domain of each receptor fused to Fc region of human IgG [10].
• In other human tissues, NPR-Bi shows strongest expression in pancreas and lung, whereas in the heart and liver NPR-B is the dominating receptor [11].
• 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% [12].
• These results suggest that the actions of NPR-A and NPR-B, functional receptors in the human thyroid cell, may in part be mediated by cGMP-induced alterations in the cytoskeleton [13].

Associations of NPR2 with chemical compounds

• When intact plants were placed in darkness, there was an increase in ABA levels as well as increased levels of NPR1 and NPR2 RNA [14].
• The deduced amino acid sequences of NPR1 and NPR2 were found to share similarities with many abscisic acid-induced or seed-abundant proteins [15].
• Here, we investigated the mechanistic basis for hyperosmotic and lysophosphatidic acid-dependent inhibition of NPR-B [16].
• The conversion of this residue to alanine or glutamate did not reduce the amount of mature receptor protein as indicated by detergent-dependent guanylyl cyclase activities or Western blot analysis but completely blocked the ability of PKC to induce the dephosphorylation and desensitization of NPR-B [17].
• 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 [18].

Regulatory relationships of NPR2

• ANP and C-type natriuretic peptide (CNP) induced a concentration-dependent increase in cGMP suggesting the presence of type-A (NPR-A) and type-B (NPR-B) receptors, respectively [19].

Other interactions of NPR2

• NPR-A and NPR-B are membrane-bound guanylyl cyclases, whereas NPR-C is assumed to function as a clearance-type receptor [20].
• These findings identify the specific natriuretic peptide receptor responsible for Cl- secretion in the shark rectal gland and provide the first evidence for activation of CFTR Cl- channels by a cloned NPR-B receptor [21].
• RNase protection analysis of the eel NPR-B mRNA demonstrated that the message was predominantly expressed in the liver and atrium as well as in the gill with moderate-to-small amounts in the brain, ventricle, esophageal sphincter, stomach, posterior intestine and kidney [22].

Analytical, diagnostic and therapeutic context of NPR2

• The ANPRB gene was assigned to 9p11----p22 using species-specific length variation in PCR fragments [23].
• Western blot analysis using the purified antibody revealed that while the native NPR-B exists as an oligomer, the truncated NPR-B lacking most of its cytoplasmic domain is a monomer [24].
• Down-regulation of the biologically active binding sites (i.e. NPR-A and NPR-B) could explain the blunted response to cardiac natriuretic hormones observed in heart failure (HF), but not the increased metabolic clearance rate [25].
• Expression of NPR-B mRNA was confirmed in GMCs by RT-PCR [26].

References