PROTEIN PHOSPHORYLATION, EPILEPSY, AND ANTICONVULSANTS

获得癫痫的分子洞察力并开发最佳疗法 对于癫痫，了解癫痫发作的基本过程是很重要的。 调节神经元兴奋性和病理过程如何相互作用 具有控制神经元活动的正常调节机制。 虽然 兴奋性调节的精确分子方面并不 众所周知，最近的进展已经在理解的作用， 钙离子是神经元中的主要第二信使， 兴奋性 Ca 2 +-钙调蛋白依赖性蛋白激酶（CaM激酶II）具有 参与调节Ca 2+对细胞的某些作用， 功能和神经元兴奋性。 这项研究工作将 测试假设CaM激酶II参与介导一些 Ca ~（2+）对特定膜离子电导的调节作用。 这 该项目将协调生物化学，免疫细胞化学和 电生理学研究，以确定内源性CaM激酶II是否 介导的影响，Ca 2+对特定的离子电导， 裸鳃类软体动物（Hermissenda crassicornis）的神经元。 我们 短期目标是a）表征外源性钙调素的作用 激酶II对鉴定的神经元中比离子电导的影响，B） 内源性CaM激酶II活性鉴定和表征 这些神经元，和c）免疫细胞化学研究，采用单克隆 抗体以确定CaM的细胞和亚细胞分布 这些神经元中的激酶II。 长期目标是a）调查 神经元兴奋是否可以调节CaM激酶II的活性， 采用体内磷酸化研究，B）表征 以前已经证明的单克隆抗体的作用， 通过特定离子电导调节CaM激酶II活性，和c） 药物对内源性钙调素影响的相关性 激酶II活性及其对特定离子电导的影响 神经元 这些结果可能提供了一个内源性的分子洞察力， 调节Ca ~（2+）对神经元某些作用的机制 兴奋性，并可能增加我们对复杂机制的理解 癫痫发作放电的发病机制及其调节机制 抗惊厥化合物

To obtain a molecular insight into epilespy and develop optimal therapies for seizure disorders, it is important to understand the basic processes regulating neuronal excitability and how pathological processes interact with normal modulatory mechanisms that control neuronal activity. Although the precise molecular aspects of the regulation of excitability are not known, recent advances have been made in understanding the role that calcium, a major second messenger in neurons, plays in regulating neuronal excitability. Ca2+-calmodulin dependent protein kinase (CaM kinase II) has been implicated in regulating some of the effects of Ca2+ on cellular function and neuronal excitability. Studies in this research effort will test the Hypothesis that CaM kinase II is involved in mediating some of the regulatory effects of Ca2+ on specific membrane ion conductances. This project will coordinate biochemical, immunocytochemical and electrophysiological studies to determine whether endogenous CaM kinase II mediates the effects of Ca2+ on specific ion conductances in identified neurons of the nudibranch mollusc, Hermissenda crassicornis. Our Short-Term Goals are a) characterization of the effects of exogenous CaM kinase II on specific ion conductance in identified neurons, b) identification and characterization of endogenous CaM kinase II activity in these neurons, and c) immunocytochemical studies employing monoclonal antibodies to ascertain the cellular and subcellular distribution of CaM kinase II in these neurons. The Long Term Goas are a)investigation of whether neuronal excitation can modulate the activity of CaM kinase II, employing in vivo phosphorylation studies, b) characterization of the effects of monoclonal antibodies that have previously been demonstrated to regulate CaM kinase II activity on specific ion conductances, and c) correlation of the effects of pharmacological agents on endogenous CaM kinase II activity with their effects on specific ion conductances in neurons. The results may provide a molecular insight into an endogenous mechanism for modulating some of the effects of Ca2+ on neuronal excitability and may increase our understanding of the complex mechanisms that underlie the pathogenesis of seizure discharge and its regulation by anticonvulsant compounds.