Regulation of the Atrial Natriuretic Peptide Receptor

描述（由申请人提供）：超过5000万美国人的血压超出了安全的生理范围，这一过程被称为高血压。长期高血压引起心脏负荷过重，导致心室重构和心脏纤维化。对抗这些潜在致命后果的激素被称为利钠肽。当血压升高时，心钠肽（ANP）和脑钠肽（BNP）从心脏分泌，刺激血管松弛和体液流失。另一方面。c型利钠肽（CNP）高度集中于内皮细胞，并以旁分泌方式调节血管平滑肌细胞的张力和增殖。ANP和BNP的信号受体是利钠肽受体。(美国国家公共电台。A)，然而，利钠肽受体- b （NPR-B）是CNP的信号受体。这两种受体都由细胞外配体结合域、单一跨膜区域、细胞内激酶同源性和冠酰环化酶催化域组成。后者合成胞内信号分子cGMP，介导利钠肽的大部分作用。NPR-A和NPR-B的激酶同源结构域的磷酸化对它们的活性至关重要。相反，在长时间暴露于利钠肽（同源脱敏）或激活蛋白激酶c的药物时，去磷酸化会使这些受体关闭。然而，关于从这些受体中去除磷酸盐的分子的信息很少。同样，去磷酸化是否介导由血管活性激素（如血小板源性生长因子或鞘氨醇-1-磷酸）引发的NPR-B脱敏尚不清楚。为了回答这些问题，提出了以下具体目标：A)表征使NPR-AB脱磷酸化的磷酸酶)确定Ser-523的脱磷酸化对于NPR-BC的异源脱敏是否必要和充分)定义npr - b异源脱敏所需的信号转导途径。这些目标的执行将导致实现本提案的广泛、长期目标。我们要发展对利钠肽受体磷酸化依赖性调节的分子理解，并将这一知识作为开发有效治疗心血管疾病的药物的垫脚石。

DESCRIPTION (provided by applicant): 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.