Regulation of the Atrial Natriuretic Peptide Receptor

描述(由申请者提供)：超过5000万美国人的血压超出了安全的生理范围，这一过程称为高血压。长期的高血压会导致心脏超负荷，从而导致心室重构和心脏纤维化。对抗这些潜在致命后果的荷尔蒙被称为利钠肽。当血压升高时，心脏会分泌心钠素(ANP)和脑利钠肽(BNP)，刺激血管松弛和液体流失。从另一方面来说。C型利钠肽(CNP)在血管内皮细胞中高度集中，以旁分泌的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A(NPR.A)，而利钠肽受体B(NPR-B)是CNP的信号受体。这两种受体都由一个胞外配体结合区、一个单一的跨膜区域、胞内同源蛋白和鸟苷酸环化酶催化区组成。后者合成细胞内的信号分子cGMP，它介导了利钠肽的大部分作用。NPR-A和NPR-B的激酶同源域的磷酸化对它们的活性是必不可少的。相反，去磷酸化会关闭这些受体，以响应长时间的钠尿肽暴露(同源脱敏)或激活蛋白激酶C的药物。然而，关于从这些受体上去除磷酸盐的分子的信息很少。同样，去磷酸化是否介导了由血管活性激素如血小板衍生生长因子或1-磷酸鞘氨醇引起的NPR-B的脱敏尚不清楚。为了回答这些问题，提出了以下具体目标：a)确定使NPR-AB去磷酸化的磷酸酶的特性)确定Ser-523的去磷酸化对于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通路。这些目标的实现将导致实现这项建议的广泛的、长期的目标，即发展对磷酸化的钠尿肽受体的依赖调节的分子理解，并将这一知识用作开发有效的治疗心血管疾病的治疗药物的踏脚石。

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.