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 万美国人的血压超出安全生理范围，这一过程称为高血压。 长期高血压会导致心脏超负荷，从而导致心室重塑和心脏纤维化。 对抗容量超负荷这些潜在致命后果的激素称为利钠肽。 为了应对血压升高，心脏分泌心房钠尿肽 (ANP) 和脑钠尿肽 (BNP)，刺激血管舒张和体液流失。 另一方面。 C型利钠肽（CNP）高度集中在内皮细胞中，以旁分泌方式调节血管平滑肌细胞的张力和增殖。 ANP 和 BNP 的信号传导受体是利钠肽受体 A (NPR.A)，而利钠肽受体 B (NPR-B) 是 CNP 的信号传导受体。 两种受体均由胞外配体结合结构域、单个跨膜区域以及胞内激酶同源性和鸟苷酸环化酶催化结构域组成。 后者合成细胞内信号分子 cGMP，介导利尿钠肽的大部分作用。 NPR-A 和 NPR-B 激酶同源结构域的磷酸化对其活性至关重要。 相反，去磷酸化会关闭这些受体，以响应长期暴露于利钠肽（同源脱敏）或激活蛋白激酶 C 的试剂。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，去磷酸化是否介导由血管活性激素（例如血小板衍生生长因子或 1-磷酸鞘氨醇）引起的 NPR-B 脱敏尚不清楚。 为了回答这些问题，提出以下具体目标：A）表征NPR-AB去磷酸化酶）确定Ser-523去磷酸化对于NPR-BC异源脱敏是否是必要和充分的）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广泛的长期目标 该提案旨在发展对利尿钠肽受体磷酸化依赖性调节的分子理解，并利用这一知识作为开发治疗心血管疾病的有效治疗药物的垫脚石。