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HORMONAL REGULATION OF PHOSPHOINOSITIDE METABOLISM

磷脂酰肌醇代谢的激素调节

基本信息

批准号：
3235640
负责人：
JOHN N FAIN
金额：
$ 14.63万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
1985
资助国家：
美国
起止时间：
1985-09-01 至 1993-03-31
项目状态：
已结题

项目摘要

The aim of these studies is to examine the hormonal regulation of phosphoinositide metabolism in rat hepatocytes and other cells. In liver, alpha-1 catecholamines and vasopressin activate glycogen phosphorylase secondary to an elevation of intracellular calcium and diacylglycerol. The rise in calcium is secondary to formation of inositol 1,4,5 trisphosphate derived from phospholipase C-induced breakdown of phosphatidylinositol 4,5- bisphosphate (PIP2) as is diacylglycerol. It is now clear that phospholipase C activity is regulated by guanine nucleotides. This project focuses on the role of guanine nucleotides in hormone induced breakdown of phosphatidyl-inositol 4,5- bisphosphate. Our long-term goal is isolation of the membrane bound phospholipase C responsible for breakdown of phosphoinositides. The requirement for guanine nucleotides suggests that a guanine nucleotide binding protein, tentatively called Np, may be involved in coupling of hormone-receptor complexes to phospholipase C. Phospholipase C activity will be examined using tritiated PIP2. We will attempt to label Np with GTP analogues and find a toxin that will ADP-ribosylate it, with the eventual aim of isolating this putative guanine nucleotide binding protein. Investigations will continue on the regulation by agonists that stimulate polyphosphoinositide breakdown, of high affinity GTPase activity in hepatocytes and other cell types. We intend to establish the identity of the guanine nucleotide binding protein involved. The inhibition by vasopressin of hepatocyte (Ca2+ Mg2+) ATPase activity will be further investigated in an attempt to elucidate the link, if any, between this effect and phosphoinositide breakdown. This project is primarily a metabolic investigation using biochemical techniques. The studies are done in experimental animals and should provide significant insights into various diseases of metabolism and especially diabetes.

这些研究的目的是检查激素调节磷酸肌醇代谢在大鼠肝细胞和其他细胞在肝脏中，α-1儿茶酚胺和加压素激活糖原磷酸化酶继发于细胞内钙和甘油二酯。钙的增加是次要的，形成肌醇1，4，5三磷酸，磷脂酶C诱导的磷脂酰肌醇4，5- 二磷酸（PIP 2），如二酰基甘油。现在已经清楚磷脂酶C活性受鸟嘌呤核苷酸调节。这个项目的重点是鸟嘌呤核苷酸在激素诱导磷脂酰肌醇4，5- 二磷酸盐我们的长期目标是分离细胞膜结合型磷脂酶C负责分解磷酸肌醇。对鸟嘌呤核苷酸的需求初步表明，存在一种鸟苷酸结合蛋白 Np可能参与了受体与受体的偶联磷脂酶C的复合物。磷脂酶C活性将使用氚化PIP 2进行检测。我们将尝试标记Np， GTP类似物，并找到一种毒素，将ADP-核糖基化，分离这种假定的鸟嘌呤核苷酸的最终目的结合蛋白调查将继续进行，刺激多磷酸肌醇分解的激动剂，在肝细胞和其他细胞类型中的亲和力GT α活性。我们旨在确定鸟嘌呤核苷酸结合的身份，蛋白质参与。加压素对肝细胞的抑制作用 (Ca2+ Mg 2+）ATP酶活性将在一个试图阐明这种影响与磷酸肌醇分解。该项目主要是一个利用生物化学技术进行代谢研究。的研究是在实验动物中进行的，应该提供对各种代谢疾病的重要见解，尤其是糖尿病。