GAMMA 2 MSH RECEPTORS, CELLULAR SIGNALING , CA2+, AND HYPERTENSION

GAMMA 2 MSH 受体、细胞信号传导、CA2 和高血压

• 批准号: 6573402
• 负责人: T. Joan Robinson
• 金额: $ 17.41万
• 依托单位: MORGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6573402
• 关键词: autoradiography; brain regulatory center; cell cell interaction; densitometry; diacylglycerols; enzyme induction /repression; hormone receptor; hormone regulation /control mechanism; hypertension; image processing; immunocytochemistry; inositol phosphates; isozymes; laboratory rat; light microscopy; melanocyte stimulating hormone; northern blottings; nucleic acid hybridization; photomicrography; proopiomelanocortin; protein kinase C; receptor binding; receptor coupling; second messengers; spontaneous hypertensive rat

Reports have shown that the regulation of cell function occurs as a result of the coupling of cell membrane receptors to the activation of protein kinases associated with the receptor or through changes in the level of second messengers. In preliminary studies, we have identified gamma-2-Melanocyte stimulating hormone (MSH) receptors in regions of the brain that have been associated with the regulation of blood pressure and behavioral function. We have also shown that gamma-2-MSH increases the level of Protein Kinase C (PKC) and decreases the level of cyclic AMP dependent Protein Kinase (PKA) in synaptosomes isolated from the forebrain, midbrain and hindbrain of Sprague Dawley rats. The increase in the activation of PKC suggest that gamma-2-MSH receptor is coupled to PKC in this system. We hypothesize that gamma-2-MSH, a proopiomelanocortin (POMC)-derived peptide with pressor, natriuretic and cardioaccelerator effects, elicits these cardiovascular effects through the activation of specific PKC's and through changes in the level of the second messengers, diacylglycerol (DAG) and inositol l,4,5-trisphosphate (IP3). Therefore, in order to test our hypothesis, we propose to (1) use receptor autoradiographic techniques to locate and quantify the microscopic distribution of gamma-2-MSH receptors in the different parts of the brain of rats in which blood pressure is regulated, (2) investigate ways in which gamma-2-MSH receptor mediated responses are facilitated through the second messengers DAG and IP3 in the regions of the brains associated with blood pressure regulation and identified in #1. This will be done by first measuring the initial basal level of DAG and IP3 and secondly, by measuring changes in the levels of DAG and IP3 following stimulation by gamma-2-MSH in the regions of the brains associated with hypertension. Further, since membrane receptors have been reported to be coupled to the activation of protein kinases, either by activating a protein kinase associated with the receptor, or through changes in the levels of second messengers we also plan to (3) Identify and localize the specific PKC isozyme(s) in the regions of the brain; and determine the activation of the specific isozymes in the presence and absence of gamma-2-MSH.

报告显示，细胞功能的调节发生在 这是细胞膜受体偶联到 激活与受体相关的蛋白激酶，或 通过改革 第二信使的水平。在初步研究中， 鉴定的γ-2-促黑素细胞激素（MSH）受体 在大脑的区域， 调节血压和行为功能。我们还 表明γ-2-MSH增加蛋白激酶C的水平， (PKC)并降低环磷酸腺苷依赖蛋白的水平 从前脑、中脑、海马和海马分离的突触体中的PKA 和Sprague道利大鼠的后脑。的增加 PKC的激活表明γ-2-MSH受体与 PKC在这个系统中我们假设γ-2-MSH，a 阿黑皮素原（POMC）衍生肽具有升压作用， 利钠利尿剂和心脏加速剂的作用， 通过激活特定的PKC的心血管效应， 通过第二信使水平的变化， 甘油二酯（DAG）和1，4，5-三磷酸肌醇（IP 3）。 因此，为了验证我们的假设，我们建议（1）使用 受体放射自显影技术定位和定量 γ-2-MSH受体在不同组织中的显微分布 大鼠大脑中血压调节的部分， (2)研究γ-2-MSH受体介导的 通过第二信使DAG和IP 3促进响应 大脑中与血压相关的区域 #1中的规则和标识。这将首先完成 测量DAG和IP 3的初始基础水平，其次，通过 测量DAG和IP 3水平的变化， γ-2-MSH在脑相关区域的刺激 高血压此外，由于膜受体已经被 据报道，与蛋白激酶的活化偶联， 通过激活与受体相关的蛋白激酶，或 通过改变第二信使的水平， (3)确定和定位特定的PKC同工酶（s）在 大脑区域;并确定特定的激活 在存在和不存在γ-2-MSH的情况下的同工酶。