MOLECULAR AND CELLULAR ANALYSIS OF BRAIN ENRICHED PTPS

脑富集 PTPS 的分子和细胞分析

• 批准号: 6639036
• 负责人: Paul J Lombroso
• 金额: $ 33.47万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6639036
• 关键词: NMDA receptors; affinity chromatography; biological signal transduction; corpus striatum; dopamine receptor; electrophysiology; enzyme activity; enzyme mechanism; enzyme substrate; immunoprecipitation; isozymes; laboratory rat; neurochemistry; phosphorylation; protein localization; protein protein interaction; protein tyrosine phosphatase; proteolysis; voltage /patch clamp; yeast two hybrid system

DESCRIPTION (from applicant's abstract): This R01 application focuses on the role of protein tyrosine phosphatases (PTPs) in signal transduction pathways in the basal ganglia. Compeling evidence suggests that the basal ganglia are involved in a number of neuropsychiatric disorders, including schizophrenia, Tourette's syndrome and obsessive compulsive disorder. In Huntington and Parkinson's disorders, abnormalities of the basal ganglia, or in their efferent and afferent pathways have been found. This collection of nuclei are also the site of action for many of the unwanted side effects of neuroleptic drugs. Disruption of the neural signaling mechanisms within the basal ganglia is a common component of all of these disorders, and further knowledge is needed of the normal signaling pathways that occur in this region of the CNS. The long-term goal of my research are to characterize genes that contribute to neuropsychiatric disorders. Under previous funding mechanisams (a K20 and then a FIRST award from NIMH), my laboratory has isolated a novel family or protein tyrosine phosphatases (PTPs) uniquely present within dopaminoceptive neurons of the basal ganglia and related structures. As the protein is highly enriched within rat striatum, it is termed STEP for Striatal Enriched Phosphatase. The present application is a natural continuation of my FIRST Award in which we isolated four isoforms of the STEP family. The first specific aim proposes to continue to isolate the characterize members of this large and important group of PTPs. The family consists of cytosolic and membrane-associated isoforms, as well as truncated forms that lack on active catalytic siste. One of the most striking features is that some STEPs contain transmembrane domains, PEST sequences, and polyproline-rich sequences. We hypothesize that these provide a mechanism for the subcellular targeting of STEP members, for the regulation of their enzymatic activity, and for their substrate specificity. In addition, we propose that phosphorylation asnd proteolysis of STEP occurs after dopamine D1 signaling. We will identify the physiological substrates of STEP, one of which is proposed to be the NMDA receptor. We will these these hypotheses using biochemical, molecular, and electrophysiological techniques.

描述（来自申请人摘要）： 此R01应用程序的重点是蛋白酪氨酸磷酸酶的作用 （PTPs）在基底神经节信号转导通路中的作用。有力的证据 表明基底神经节参与了许多神经精神疾病， 疾病，包括精神分裂症、抽动秽语综合症和强迫症 强迫症在亨廷顿和帕金森氏症中， 基底神经节，或在其传出和传入通路已被发现。 这些细胞核的集合也是许多不需要的 精神抑制药的副作用神经信号的中断 基底神经节内的机制是所有这些的共同组成部分， 疾病，需要进一步了解正常的信号通路 发生在中枢神经系统的这个区域。 我研究的长期目标是描述基因， 神经精神疾病。根据以前的供资机制（K20，然后 我的实验室已经分离出一个新的家族或蛋白质， 酪氨酸磷酸酶（PTPs）是唯一存在于多巴胺感受神经元内的 基底神经节和相关结构。由于蛋白质高度富集 在大鼠纹状体内，它被称为STEP，即纹状体富集磷酸酶。 本申请是我的第一个裁决的自然延续，其中我们 分离了STEP家族的四种同种型。第一个具体目标建议， 继续孤立这个庞大而重要的集团的特征成员 的PTPs。该家族由胞质和膜相关亚型组成，如 以及缺乏活性催化活性的截短形式。一个最 一个显著的特征是一些STEPs含有跨膜结构域，PEST 序列和富含聚脯氨酸的序列。我们假设这些提供了一个 STEP成员的亚细胞靶向机制， 它们的酶活性和它们的底物特异性。另外我们 提出STEP的磷酸化和蛋白水解发生在多巴胺D1 发信号。我们将确定STEP的生理底物，其中之一是 被认为是NMDA受体。我们将这些假设用 生物化学、分子和电生理学技术。