Regulation of the Atrial Natriuretic Peptide Receptor

心房钠尿肽受体的调节

• 批准号: 6543274
• 负责人: Lincoln Ross Potter
• 金额: $ 24.98万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6543274
• 关键词: atrial natriuretic peptide; cyclic GMP; enzyme activity; enzyme induction /repression; guanylate cyclase; hormone receptor; phosphorylation; protein isoforms; protein structure function; receptor binding; receptor expression; receptor sensitivity; site directed mutagenesis; tissue /cell culture

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.

描述（由申请人提供）：超过5000万美国人表现出在安全生理范围之外的血压，这是一个称为高血压的过程。 长时间的高血压会诱导心脏超负荷，从而导致心室重塑和心脏纤维化。 应对这些潜在致命后果的激素被称为纳特里尔肽。 由于血压的响应，心房利尿肽（ANP）和脑脂肪酸肽（BNP）被从心脏中分泌，并刺激血管瘤和液体丧失。 另一方面。 C型亚钠肽（CNP）在内皮细胞中高度浓缩，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的信号传导受体是Natriuretic肽受体。A（NPR.A），而Natriuretic肽受体-B（NPR-B）是CNP的信号传导受体。 两种受体都由细胞外配体结合结构域，一个跨膜区域以及细胞内激酶同源性和瓜尼酶环化酶催化结构域组成。 后者合成了细胞内信号分子CGMP，该分子介导了纳二尿素肽的大多数作用。 NPR-A和NPR-B的激酶同源域的磷酸化对于它们的活性至关重要。 相反，脱磷酸化以响应于长时间的亚钠肽暴露的同源脱敏）或激活蛋白激酶C的药物而关闭这些受体。但是，几乎没有关于从这些受体中去除磷酸盐的分子的信息。 同样，脱磷酸化是否介导了血管活性激素引起的NPR-B的脱敏，例如血小板衍生的生长因子或鞘氨醇-1-磷酸盐。 要回答这些问题，提出了以下具体目的：a）表征将npr-ab的磷酸酶的表征确定SER-523的去磷酰化是否是必需的且足够的，对于NPR-BC的脱敏性，定义了信号传输途径所需的npr降低途径，将其延伸到npr body the npr body tear thul n pr botimitive thul n pr botive thul n pr botive them npr botive thul n pr bodimitive thud npr botive的执行的执行，这是必不可少的。该建议是对磷酸化的分子理解。依赖性纳妥肽受体的调节，并将这些知识用作垫脚石，以开发有效的治疗剂来治疗心血管疾病。