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

有报道表明，细胞功能的调节是这样发生的 细胞膜受体偶联到 与受体或受体相关的蛋白激酶的激活 通过更改 第二信使的级别。在初步研究中，我们有 已鉴定的γ-2-黑素细胞刺激素(MSH)受体 在大脑中与大脑相关的区域 调节血压和行为功能。我们还有 显示伽马-2-MSH增加了蛋白激酶C的水平 (PKC)，并降低cAMP依赖蛋白水平 分离自前脑、中脑的突触体中的PKA 和SD大鼠的后脑。收入的增加 PKC的激活提示γ-2-MSH受体偶联到 PKC在本系统中的应用。我们假设伽马-2-MSH，一个 有升压作用的前阿片黑素皮质素(POMC)衍生肽， 利钠和心脏加速剂的作用，引起这些 激活特定的PKC和PKC对心血管的影响 通过改变第二信使的级别， 甘油二酯和肌醇L，4，5-三磷酸(IP3)。 因此，为了检验我们的假设，我们建议(1)使用 受体放射自显影技术用于定位和定量 不同组织中γ-2-MSH受体的微观分布 大鼠大脑中调节血压的部分， (2)探讨γ-2-MSH受体介导的途径 通过第二信使DAG和IP3促进响应 在大脑中与血压相关的区域 规定，并在#1中确定。这将在第一个 测量DAG和IP3的初始基础水平，其次，通过 测量以下DAG和IP3水平的变化 γ-2-MSH对大脑相关区域的刺激 患有高血压。此外，由于膜受体已经被 据报道，它与蛋白激酶的激活有关， 通过激活与受体相关的蛋白激酶，或 通过改变第二信使的级别，我们也计划 (3)鉴定和定位黄瓜中特异的PKC同工酶(S)。 大脑的各个区域；并确定特定的 在存在和不存在γ-2-MSH的情况下的同工酶。

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.