Slick and Slack Heteromers in Neuronal Excitability

描述（由申请人提供）：KNa通道由细胞内钠激活，仅显示弱电压依赖性。编码这些通道的两个基因Slack和Slick在某些大脑区域显示出重叠的mRNA和蛋白质表达，最明显的是在听觉和嗅觉系统中。Slack和Slick通道在其激活动力学和对细胞内氯、ATP和PKC的敏感性方面存在显著差异。该建议的具体目标将确定它们是否形成异聚体通道，这些通道有助于斜方体内侧核（MNTB）的主要听觉神经元中的天然KNa电流。这项建议将针对三个具体目标。目的1将确定Slack和Slick是否在异源表达系统中形成异聚体通道。在目标2中，我们将评估的作用，光滑和松弛亚基的MNTB的主要神经元的本地KNa电流。具体来说，我们将测试这样的假设，即Slick和Slack电流水平有助于不同模式的动作电位放电的时间准确性， 不同的刺激频率。目的3研究PKC对Slack和Slick神经元兴奋性调节的生理意义。实验将采用分子生物学、电生理学和Na+成像技术。这个提议的目的是确定KNa在听觉神经元中的作用，从而增加我们对听觉网络特性的理解。我们相信，这将导致潜在的，治疗目标的病理条件，如所看到的听觉超敏门刻板运动自闭症 行为模式进一步了解正常的感觉编码可能对我们理解自闭症和其他重叠疾病，如脆性X综合征，Reft综合征和脑硬化症有深远的影响。此外，推进这类独特的通道的知识，将在所有的可能性导致治疗干预，由于其在缺氧和脑缺血的假定保护作用。此外，它们的药理学活化将使它们成为控制癫痫发作活性的靶点。

DESCRIPTION (provided by applicant): KNa channels are activated by intracellular sodium and show only weak voltage dependence. The two genes which encode these channels, Slack and Slick, show overlapping mRNA and protein expression in certain brain regions, most notably in the auditory and olfactory systems. Slack and Slick channels differ significantly in their activation kinetics and their sensitivity to intracellular chloride, ATP and PKC. The specific aims of this proposal will determine whether they form heteromeric channels which contribute to native KNa currents in principal auditory neurons of the medial nucleus of the trapezoid body (MNTB). This proposal will address three specific aims. Aim 1 will determine whether Slack and Slick form heteromeric channels in heterologous expression systems. In Aim 2 we will assess the role of Slick and Slack subunits in the native KNa current of principal neurons of the MNTB. Specifically, we will test the hypothesis that Slick and Slack current levels contribute to the temporal accuracy of different patterns of action potential firing at different stimulation frequencies. Aim 3 will study the physiological significance of PKC modulation of Slack and Slick in regulating the excitability of native neurons. Experiments in this proposal will use techniques of molecular biology, electrophysiology and Na+ imaging. The purpose of this proposal is to identify the role of KNa in auditory neurons and consequently increase our understanding of auditory network properties. It is our belief that this will lead to potential, therapeutic targets for pathological conditions such as are seen when auditory hypersensitivity gates stereotypic motor autistic behavior patterns. Furthering our understanding of normal sensory encoding could have far reaching implications towards our understanding of Autism and other overlapping conditions such as Fragile X syndrome, Reft syndrome and Tuberous sclerosis complex. In addition, advancing the knowledge of this unique class of channels will in all likelihood lead to therapeutic interventions due to their putative protective roles in hypoxia and cerebral ischemia. Moreover, their pharmacological activation would make them a target for control of epileptic seizure activity.