CALMODULIN DEPENDENT KINASE AND SYNAPTIC FUNCTION

一种II型钙/钙调蛋白依赖性蛋白激酶（CaM激酶 II）磷酸化细胞骨架蛋白作为主要底物 高度集中在神经元，包括突触后 密度（PSD）。 全酶含有两个自磷酸化， 钙调蛋白结合亚基的50 KDa和60 KDa， 在发育过程中差异表达，并存在于可变的 不同脑区的比例。 拟议的目标之一 项目的目的是确定每个子单元是否自主运行。 主要的50 KDa亚基是主要的突触后密度蛋白 （mPSDp），其占PSD的16-50%。 金额50 PSD中的KDa/mPSDp在出生后发育过程中发生变化， 感官剥夺，当动物被放置在丰富的 环境，这表明CaM激酶II起着重要的作用， 在突触功能上。 在突触处还存在 微管相关蛋白2（MAP 2）和神经丝（NF） 蛋白质，其是激酶的细胞骨架蛋白质底物。 MAP 2和NF在体内都是磷酸化的，但其位点 特异性、磷酸化作用或生理相关性 涉及的激酶是未知的。 第二个目标是确定 CaM激酶II对这些蛋白质功能的影响。 还有， i不知道是否在磷酸化状态的变化， 激酶和/或其底物蛋白影响突触功能。 该项目的最终目标是确定CaM激酶是否 与胞质激酶相比，PSD中的II发生了改变， 建立一个模型来阐明CaM激酶II在突触中的作用， 功能 目前的工作假设是，CaM激酶 PSD中的II是高度磷酸化的， 稳定PSD作为神经元中的结构成分。 私营部门司的稳定可能对建立和 维持突触前和突触后之间的突触接触 神经元 内源性MAP 2的磷酸化预计会减少 MAP 2/蛋白质和MAP 2/膜的相互作用，这可能是 对蛋白质和膜周转很重要。 磷酸化 通过CaM激酶II的神经丝蛋白可以稳定 神经丝 建议的项目将有助于我们 了解几种神经系统疾病， 在神经元细胞骨架和/或突触神经传递中， 观察，包括阿尔茨海默病，癫痫肌萎缩 脊髓侧索硬化症和关岛型帕金森综合征。

A Type II calcium/calmodulin-dependent protein kinase (CaM kinase II) that phosphorylates cytoskeletal proteins as major substrates in highly concentrated in neurons, including the postsynaptic density (PSD). The holoenzyme contains two autophosphorylating, calmodulin-binding subunits of 50 KDa and 60 KDa that are differentially expressed during development and exist in variable proportions in different brain regions. One goal of the proposed project is to determine if each subunit functions autonomously. The major 50 KDa subunit is the major postsynaptic density protein (mPSDp) that comprises 16-50% of the PSD. The amount of 50 KDa/mPSDp in the PSD is altered during post-natal development, sensory deprivation, and when animals are placed in enriched environments, suggesting that CaM kinase II plays an important role in synaptic function. Also present at the synapse are the microtubule-associated protein 2 (MAP 2) and neurofilament (NF) proteins, which are cytoskeletal protein substrates for the kinase. Both MAP 2 and NF are phosphorylated in vivo, but the site specificity, effect of phosphorylation, or physiologically relevant kinase involved are unknown. A second goal is to determine the effects of CaM kinase II on the function of these proteins. Also, i is not known whether changes in the phosphorylation state of the kinase and/or its substrate proteins affects synaptic function. The final goals of the project are to determine whether CaM kinase II in the PSD is altered compared to the cytosolic kinase, and to develop a model to elucidate the role of CaM kinase II in synaptic function. The working hypothesis in the present proposal is that CaM kinase II in the PSD is highly-phosphorylated, and that phosphorylation stabilizes the PSD as a structural component in neurons. Stabilization of the PSD may be important in the establishment and maintenance of synaptic contact between the pre- and postsynaptic neurons. Phosphorylation of endogenous MAP 2 is expected to reduce MAP 2/protein and MAP 2/membrane interactions which may be important for protein and membrane turnover. Phosphorylation of neurofilament proteins by CaM kinase II may stabilize neurofilaments. The proposed project will contribute to our understanding of several neurological disorders where alterations in the neuronal cytoskeleton and/or synaptic neurotransmission are observed, including Alzheimer's disease, epilepsy amyotrophic lateral sclerosis and the Guam form of Parkinsonism.