THE ROLE OF BRAIN SPECIFIC PROTEINS IN NERVE FUNCTION

二价阳离子，即钙离子，长期以来一直被认为是主要的 刺激引起细胞反应的细胞内信号，如 内吞和胞吐、运动、中间代谢的改变以及 扩散。然而，生物化学机制通过它 刺激诱导的游离钙离子浓度的通量与细胞偶联 监管直到最近才被阐明。在这个和其他领域工作 实验室发现钙调蛋白(CaM)是一种主要的细胞内受体 在真核生物中寻找这些钙离子调节信号。这方面和其他方面的研究 在重要性和进展报告中总结的实验室提供了 关于Cam行动的一般机制的大量信息。 然而，关于确切的分子的信息有限。 提供CaM-酶相互作用的结构或这种相互作用如何 诱导酶的激活。这样的信息对于理解 钙依赖的调节，并阐明潜在的功能障碍 监管是疾病过程中的致病因素。的主要目标是 在方法中提出的研究计划是揭示结构相互作用 钙调素和钙调素调节的酶导致钙-钙依赖刺激 酶活性。结构、生化和免疫学研究，旨在 为了进一步了解这些过程，建议包括：1) 原生动物、植物的详细比较结构分析，如果分离， 原核细胞的CaM和相似但不同的钙结合蛋白。 优雅的和脊椎动物的光滑肌肉。2)研究CaM在细胞周期中的确切作用 调节睫状肌动力蛋白ATPase活性。3)详细分析，使用 固定化吩噻嗪类抗精神病药的作用机制 CaM和其他可能与吩噻嗪结合的蛋白质 具体地说。4)详细的化学、酶学和免疫学研究 一些受CaM调控的酶中的CaM结合域。

The divalent cation, Ca2 ions, has long been recognized as a primary intracellular signal through which stimuli evoke cellular responses such as endo- and exocytosis, motility, alterations in intermediary metabolism, and proliferation. However, the biochemial mechanisms through which stimulus-induced fluxes in free Ca 2 ion concentration are coupled to cellular regulation have only recently been elucidated. Work in this and other laboratories has revealed calmodulin (CaM) to be a major intracellular receptor in eukaryotes for these Ca2 ion-regulatory signals. Studies in this and other laboratories summarized in Significance and Progress Report, have provided substantial information concerning the general mechanism through which CaM acts. However, limited information is available concerning the exact molecular structures which provide for CaM-enzyme interaction or how this interaction induces enzyme activation. Such information is essential to understand Ca-dependent regulation and to elucidate potential dysfunctions in this regulation which are causative factors in disease processes. The major goal of the research plan presented in Methods is to reveal the structural interactions of CaM and CaM regulated enzymes which result in Ca.CaM-dependent stimulation of enzyme activity. Structural, biochemical and immunological studies, designed to yield a further understanding of these processes, are proposed including: 1) Detailed comparative structural analyses of protozoan, plant and if isolated, prokaryotic CaMs and similar but distinct Ca-binding proteins found in C. elegans and vertebrate smooth muscles. 2) Studies of the exact role of CaM in regulating ciliary dynein ATPase activity. 3) Detailed analyses, using immobilized phenothiazines, of the mechanism of action of neuroleptic drugs both on CaM and other proteins which may be shown to bind phenothiazines specifically. 4) Detailed chemical, enzymological and immunological studies of the CaM binding domains in a number of CaM-regulated enzymes.