PROTEIN PHOSPHORYLATION, EPILEPSY, AND ANTICONVULSANTS

获得对癫痫的分子洞察力并开发最佳治疗方法 对于癫痫发作障碍，了解基本的过程是很重要的 调节神经元兴奋性及病理过程的相互作用 具有控制神经元活动的正常调节机制。虽然 兴奋性调控的确切分子方面并不是 众所周知，最近在理解这一角色方面取得了进展 钙是神经元中主要的第二信使，在神经元调节中发挥作用 兴奋性。钙调素依赖的蛋白激酶(CaM)II有 参与调节细胞内钙离子的某些效应 功能和神经元兴奋性。这项研究工作中的研究将 验证这一假设，即CaM激酶II参与了一些 钙离子对膜离子电导的调节作用。这 项目将协调生化、免疫细胞化学和 电生理学研究确定内源性CaM激酶II 介导Ca~(2+)对细胞内特定离子电导的影响 粗角裸目软体动物赫米森达的神经元。我们的 短期目标是a)外源CaM效应的表征 激酶II对已鉴定神经元特定离子电导的影响，b) 水稻内源CaM激酶II活性的鉴定与鉴定 这些神经元，以及c)用单克隆化的免疫细胞化学研究 确定CaM在细胞和亚细胞内分布的抗体 激酶II在这些神经元中的表达。长期目标是)调查 神经元兴奋是否能调节CaM激酶II的活性， 使用体内磷酸化研究，b)表征 先前已证实的单抗的作用 在特定的离子电导上调节CaM激酶II的活性，以及c) 药物对内源性钙调素作用的相关性 激酶II活性及其对细胞内比离子电导的影响 神经元。这一结果可能为从分子水平深入了解内源性 钙离子对神经元部分作用的调控机制 兴奋性，并可能增加我们对复杂机制的理解 这是癫痫放电的发病机制及其调节的基础。 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.