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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066397-04
Application #
6891564
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Lin, Michael
Project Start
2002-06-01
Project End
2006-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
4
Fiscal Year
2005
Total Cost
$248,889
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Biochemistry
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Flora, Darcy R; Potter, Lincoln R (2010) Prolonged atrial natriuretic peptide exposure stimulates guanylyl cyclase-a degradation. Endocrinology 151:2769-76
Dickey, Deborah M; Yoder, Andrea R; Potter, Lincoln R (2009) A familial mutation renders atrial natriuretic Peptide resistant to proteolytic degradation. J Biol Chem 284:19196-202
Bryan, Paula M; Xu, Xin; Dickey, Deborah M et al. (2007) Renal hyporesponsiveness to atrial natriuretic peptide in congestive heart failure results from reduced atrial natriuretic peptide receptor concentrations. Am J Physiol Renal Physiol 292:F1636-44
Dickey, Deborah M; Flora, Darcy R; Bryan, Paula M et al. (2007) Differential regulation of membrane guanylyl cyclases in congestive heart failure: natriuretic peptide receptor (NPR)-B, Not NPR-A, is the predominant natriuretic peptide receptor in the failing heart. Endocrinology 148:3518-22
Potter, Lincoln R; Abbey-Hosch, Sarah; Dickey, Deborah M (2006) Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr Rev 27:47-72
Bryan, Paula M; Smirnov, Dmitri; Smolenski, Albert et al. (2006) A sensitive method for determining the phosphorylation status of natriuretic peptide receptors: cGK-Ialpha does not regulate NPR-A. Biochemistry 45:1295-303
Antos, Laura K; Abbey-Hosch, Sarah E; Flora, Darcy R et al. (2005) ATP-independent activation of natriuretic peptide receptors. J Biol Chem 280:26928-32
Abbey-Hosch, Sarah E; Smirnov, Dmitri; Potter, Lincoln R (2005) Differential regulation of NPR-B/GC-B by protein kinase c and calcium. Biochem Pharmacol 70:686-94
Fan, Danhua; Bryan, Paula M; Antos, Laura K et al. (2005) 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. Mol Pharmacol 67:174-83
Potthast, Regine; Potter, Lincoln R (2005) Phosphorylation-dependent regulation of the guanylyl cyclase-linked natriuretic peptide receptors. Peptides 26:1001-8

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