Regulation of the Atrial Natriuretic Peptide Receptor

心房钠尿肽受体的调节

• 批准号: 6891564
• 负责人: Lincoln Ross Potter
• 金额: $ 24.89万
• 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/6891564
• 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5000万美国人显示血压超出安全生理范围，这一过程称为高血压。 长期高血压可引起心脏负荷过重，导致心室重塑和心脏纤维化。 对抗容量超负荷的这些潜在致命后果的激素被称为利钠肽。 作为对血压升高的响应，心房利钠肽（ANP）和脑利钠肽（BNP）从心脏分泌并刺激血管舒张和体液流失。 从另一方面来说。 C型利钠肽（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。 两种受体均由细胞外配体结合结构域、单个跨膜区、细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，其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其活性是必需的。 相反地，去磷酸化在对长时间的利钠肽暴露（同源脱敏）或激活蛋白激酶C的试剂的反应中关闭这些受体。然而，关于从这些受体中去除磷酸盐的分子的信息很少。 类似地，去磷酸化是否介导由血管活性激素（如血小板衍生生长因子或鞘氨醇-1-磷酸）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）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的异源脱敏是否是必需的和足够的）定义NPR-B的异源脱敏所需的信号转导途径这些目标的实现将导致实现本提案的广泛的、长期的目标，其目的是发展对利钠肽受体的磷酸化依赖性调节的分子理解，并将该知识用作开发用于治疗以下疾病的有效治疗剂的垫脚石：心血管疾病

项目成果

CNP, cardiac natriuretic peptide?

CNP，心利钠肽？

• DOI: 10.1210/en.2004-0181
• 发表时间: 2004
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Potter,LincolnR

Spatiotemporal regulation of the two atrial natriuretic peptide receptors in testis.

睾丸中两种心房钠尿肽受体的时空调节。

• DOI: 10.1210/en.2003-0706
• 发表时间: 2004
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Müller,Dieter;Mukhopadhyay,AmalK;Speth,RobertC;Guidone,Gabriela;Potthast,Regine;Potter,LincolnR;Middendorff,Ralf
• 通讯作者: Middendorff,Ralf

Phosphorylation-dependent regulation of the guanylyl cyclase-linked natriuretic peptide receptors.

鸟苷酸环化酶连接的利尿钠肽受体的磷酸化依赖性调节。

• DOI: 10.1016/j.peptides.2004.08.033
• 发表时间: 2005
• 期刊: Peptides
• 影响因子: 3
• 作者: Potthast,Regine;Potter,LincolnR
• 通讯作者: Potter,LincolnR