Abstract
Natriuretic peptides bind their cognate cell surface guanylyl cyclase receptors and elevate intracellular cGMP concentrations. In vascular smooth muscle cells, this results in the activation of the type I cGMP-dependent protein kinase and vasorelaxation. In contrast, pressor hormones like arginine-vasopressin, angiotensin II, and endothelin bind serpentine receptors that interact with G(q) and activate phospholipase Cbeta. The products of this enzyme, diacylglycerol and inositol trisphosphate, activate the conventional and novel forms of protein kinase C (PKC) and elevate intracellular calcium concentrations, respectively. The latter response results in vasoconstriction, which opposes the actions of natriuretic peptides. Previous reports have shown that pressor hormones inhibit natriuretic peptide receptors NPR-A or NPR-B in a variety of different cell types. Although the mechanism for this inhibition remains unknown, it has been universally accepted that PKC is an obligatory component of this pathway primarily because pharmacologic activators of PKC mimic the inhibitory effects of these hormones. Here, we show that in A10 vascular smooth muscle cells, neither chronic PKC down-regulation nor specific PKC inhibitors block the AVP-dependent desensitization of NPR-B even though both processes block PKC-dependent desensitization. In contrast, the cell-permeable calcium chelator, BAPTA-AM (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, tetraacetoxymethyl ester), abrogates the AVP-dependent desensitization of NPR-B, and ionomycin, a calcium ionophore, mimics the AVP effect. These data show that the inositol trisphosphate/calcium arm of the phospholipase C pathway mediates the desensitization of a natriuretic peptide receptor in A10 cells. In addition, we report that CNP attenuates AVP-dependent elevations in intracellular calcium concentrations. Together, these data reveal a dominant role for intracellular calcium in the reciprocal regulation of these two important vasoactive signaling systems.
Highlights
The natriuretic peptide family consists of atrial natriuretic peptide (ANP),1 B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) [1, 2]
These data indicate that NPR-B is the primary and probably the only natriuretic peptide receptor expressed in A10 cells
In this study we have shown that: 1) A10 cells express NPR-B and not Natriuretic peptide receptor A (NPR-A); 2) AVP decreases CNP-dependent but not basal cGMP levels in a time- and concentration-dependent manner; 3) the reduced cGMP concentrations are a result of decreased NPR-B guanylyl cyclase activity; 4) the NPR-B inhibition requires elevated intracellular calcium concentrations but not GF-109203X-sensitive forms of protein kinase C (PKC) or NPR-B degradation; and 5) CNP inhibits AVP-dependent intracellular calcium elevations
Summary
The natriuretic peptide family consists of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) [1, 2]. Transgenic overexpression of BNP results in skeletal overgrowth [8], and CNP, but not ANP, increases the height of the proliferative and hypertrophic chondrocyte zones in cultured tibia preparations [9] Consistent with these findings, mice lacking NPR-C display increased natriuretic peptide half-lives and skeletal overgrowth [20], whereas mice lacking either CNP [6] or type II cGMP-dependent protein kinase [21] exhibit dwarfism. The dephosphorylation of NPR-A and NPR-B in response to hormone binding has been shown to correlate with the declining activity of these receptors in whole cells [25, 27, 28], suggesting that receptor dephosphorylation mediates the homologous desensitization of these receptors Consistent with this idea, a mutant version of NPR-A that cannot be dephosphorylated is resistant to ANP-dependent desensitization in whole cells and in membrane preparations [31, 32]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
