More than 50 million Americans display blood pressures outside the safe physiological range, a process called hypertension. Prolonged hypertension induces cardiac overload, which results in ventricular remodeling and cardiac fibrosis. Hormones that combat these potentially deadly consequences of volume overload are called natriuretic peptides. In response to increased blood pressure, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are secreted from the heart and stimulate vasorelaxation and fluid loss. On the other hand. C-type natriuretic peptide (CNP) is highly concentrated in endothelial cells and regulates the tone and proliferation of vascular smooth muscle cells in a paracrine manner. The signaling receptor for ANP and BNP is the natriuretic peptide receptor.A (NPR.A), whereas, natriuretic peptide receptor-B (NPR-B) is the signaling receptor for CNP. Both receptors consist of an extracellular ligand-binding domain, a single membrane-spanning region, and intracellular kinase homology and guanylyl cyclase catalytic domains. The latter synthesizes the intracellular signaling molecule, cGMP, which mediates the majority of the effects of natriuretic peptides. Phosphorylation of the kinase homology domains of NPR-A and NPR-B is essential for their activity. Conversely, dephosphorylation turns these receptors off in response to prolonged natriuretic peptide exposure homologous desensitization) or agents that activate protein kinase C. However, little information is available concerning the molecules that remove the phosphate from these receptors. Similarly, whether dephosphorylation mediates the desensitization of NPR-B that is elicited by vasoactive hormones, such as platelet-derived growth factor or sphingosine-1-phosphate is not known. To answer these questions, the following specific aims are proposed:A) Characterize the phosphatases that dephosphorylate NPR-AB) Determine if dephosphoiylation of Ser-523 is necessary and sufficient for the heterologous desensitization of NPR-BC) Define the signal transduction pathways required for the heterologous desensitization of NPR-BThe execution of these aims will lead to the achievement of the broad, long-term objectives of this proposal, which are to develop a molecular understanding of the phosphorylation.dependent regulation of natriuretic peptide receptors and to use this knowledge as a stepping stone towards the development of effective therapeutic agents for the treatment of cardiovascular diseases.
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