THE ROLE OF BRAIN SPECIFIC PROTEINS IN NERVE FUNCTION

二价阳离子，Ca 2离子，长期以来被认为是主要的 刺激通过其引起细胞反应细胞内信号， 内分泌和胞吐、运动性、中间代谢的改变，以及 增殖 然而，通过生物化学机制， 刺激诱导的游离钙离子浓度通量耦合到细胞内 监管只是最近才被阐明。 工作在这个和其他 实验室已经揭示钙调素（CaM）是一种主要的细胞内受体 在真核生物中这些钙离子调节信号。 在这方面的研究和其他 在意义和进展报告中总结的实验室，提供了 关于CaM作用的一般机制的实质性信息。 然而，有限的信息是关于确切的分子 提供CaM-酶相互作用的结构或这种相互作用如何 诱导酶活化。 这些信息对于理解 钙依赖性调节和阐明潜在的功能障碍， 调节是疾病过程中的致病因素。 的主要目标 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。钙调素依赖的刺激， 酶活性 结构、生物化学和免疫学研究，旨在 产生这些过程的进一步理解，建议包括：1） 原生动物、植物和（如果分离）的详细比较结构分析， 原核CaMs和在C. 线虫和脊椎动物平滑肌。 2)钙调素的确切作用的研究 调节纤毛动力蛋白ATP酶活性。 3)详细分析，使用 固定化吩噻嗪类药物的作用机制， 对钙调素和其他蛋白质，可能显示出结合吩噻嗪 具体来说 4)详细的化学，酶学和免疫学研究， 在许多钙调素调节酶的钙调素结合域。

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.