Disease relevance of Npr2

• CONCLUSIONS: The results show that diabetes in mice confers increased NPR-B gene expression in the heart, suggesting that increased NPR-B signalling may affect development of diabetic cardiomyopathy [1].
• Our results may explain one of the molecular mechanisms of the growth stimulating action of CNP and suggest that activation of the CNP/GC-B pathway may be effective as a novel therapeutic strategy for achondroplasia [2].
• In humans, homozygous NPR-B mutations are the cause of acromesomelic dysplasia, Maroteaux type (AMDM), a severe form of disproportionate dwarfism [3].
• They suggest that the effects of S1P on vascular disease and wound healing may be mediated in part through inhibition of NPR-B [4].

High impact information on Npr2

• C-type natriuretic peptide (CNP) is a newly identified molecule that regulates endochondral bone growth through GC-B, a subtype of particulate guanylyl cyclase [5].
• 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 [6].
• These abnormal phenotypes are controlled by an autosomal recessive gene (cn) [7].
• Calcium-dependent dephosphorylation mediates the hyperosmotic and lysophosphatidic acid-dependent inhibition of natriuretic peptide receptor-B/guanylyl cyclase-B [8].
• Regulation of the guanylyl cyclase-B receptor by alternative splicing [9].

Biological context of Npr2

• Genetic mapping of the C-type natriuretic peptide receptor (Npr2) gene to mouse chromosome 4 [10].
• CONCLUSIONS: Taken together these data suggest that permanent removal of ANP from the natriuretic peptide system results in an up-regulation of GC-A and GC-B, and a corresponding down-regulation of C-receptor in the lung of proANP gene disrupted mice [11].
• These peptides can influence body fluid homeostasis and blood pressure control through the activation of two guanylyl cyclase (GC)-coupled natriuretic peptide receptor subtypes-GC-A and GC-B [12].
• This could indicate a defined biological function of the CNP/GC-B/cGMP axis in gestation e.g. antagonizing vasoconstrictive peptides like angiotensin II [13].
• Importantly, CNP has also become a peptide with a distinct role in male reproductive processes, since endocrine function of the testis and the regulation of penile erection are regulated by the CNP/GC-B axis [13].

Anatomical context of Npr2

• In cultured chondrocytes of cn/cn mice, stimulus with CNP did not significantly increase intracellular cGMP concentration, whereas it increased in +/+ mice [7].
• A considerable amount of GC-B mRNA was present in fetal mouse tibias [14].
• Relative expression levels of GC-B1, GC-B2, and GC-B3 vary across tissues and as a function of in vitro culture; the relative amount of GC-B2 to GC-B1 is repressed in cultured smooth muscle cells relative to endogenous ratios in the medial layer cells of the aorta [9].
• 5. In the PNS, NPR-B and NPR-C transcripts were highly expressed in dorsal root sensory (DRG) and cranial ganglia beginning at E10.5, with NPR-C signal also prominent in adjoining nerves, consistent with Schwann cell localization [15].
• Therefore, some or all of the GC-B receptor appears to exist on the apical membrane of uterine epithelial cells [16].

Associations of Npr2 with chemical compounds

• Mice with STZ-induced type-I diabetes also showed an increase of heart NPR-B mRNA expression at 12 weeks, but not at 3, 6 or 9 weeks after STZ-treatment [1].
• This could be due to the lesser availability of the peptides for binding to NPR-A or NPR-B or to an inhibitory effect on NP-dependent guanylate cyclase activity via the activation of NPR-C [17].
• We have also demonstrated that GC of NPR-B is sensitive to methylene blue [18].
• The effects of the mitogens on cellular cyclic GMP are fully explained by a direct and stable inactivation of GC-B [19].
• The activity of natriuretic peptide receptor-B (NPR-B) was unchanged after the addition of retinoid to the culture system [20].

Physical interactions of Npr2

• GC-B2 binds CNP, but the ligand fails to activate the cyclase, while GC-B3 fails to bind ligand [9].

Regulatory relationships of Npr2

• The NPR-A is selectively expressed by LLC-PK1 epithelial cells and the NPR-B by NIH-3T3 fibroblast cells [18].
• We conclude that CNP is synthesized in the pituitary, where it is located predominantly in gonadotropes, and GC-B receptors expressed in the pituitary mediate the direct effects of CNP in gonadotropes [21].

Other interactions of Npr2

• Guanylyl cyclase-B (GC-B) is a single transmembrane receptor that binds C-type natriuretic peptide (CNP) [9].
• The biological actions of natriuretic peptides are thought to be mediated through the activation of two guanylyl cyclase (GC)-coupled receptor subtypes (GC-A and GC-B) [14].
• Here we demonstrate that marked elevations of cyclic GMP induced by C-type natriuretic peptide (CNP), the ligand of GC-B, blocks activation of the mitogen-activated protein kinase cascade in fibroblasts [19].

Analytical, diagnostic and therapeutic context of Npr2

• Macrophages were shown to express all three natriuretic peptide receptors (NPR-A, NPR-B, NPR-C) using RT-PCR technique [22].
• To unravel the functions of the receptor, we generated mice lacking guanylyl cyclase B through gene targeting [23].
• Western blot analysis demonstrated that the level of GC-B, a particulate guanylyl cyclase specific for CNP, was not changed by treatment with FGFs [2].
• Its specific guanylyl cyclase-containing receptor, GC-B, is also expressed on several anterior pituitary cell types, and CNP potently stimulates cGMP accumulation in rat pituitary cell cultures and pituitary cell lines [24].
• By immunoblotting, immunohistochemical analyses and affinity crosslinking experiments, respectively, the presence of soluble guanylate cyclase (sGC), the NO receptor, and of guanylate cyclase B (GC-B), representing the CNP receptor, was demonstrated in Leydig cells, seminiferous tubules and blood vessels of the human testis [25].

References