Slick and Slack Heteromers in Neuronal Excitability

描述(申请人提供)：KNA通道由细胞内钠激活，仅表现出微弱的电压依赖性。编码这些通道的两个基因，Slack和Slick，在大脑的某些区域显示出重叠的mRNA和蛋白质表达，最明显的是在听觉和嗅觉系统。SLACK和SLICK通道在激活动力学和对细胞内氯离子、ATP和PKC的敏感性方面存在显著差异。这一提议的具体目的将决定它们是否在斜方体内侧核(MNTB)的主听神经元上形成有助于自然KNA电流的异构体通道。这项提案将涉及三个具体目标。目的1确定Slack和Slick在异源表达系统中是否形成异构体通道。在目标2中，我们将评估SLICK和SLACK亚基在MNTB主神经元天然KNA电流中的作用。具体地说，我们将测试这一假设，即SLICK和SLACK电流水平有助于不同模式的动作电位激发的时间准确性 不同的刺激频率。目的3研究Slack和SLICK的PKC调控在调节神经元兴奋性中的生理意义。这项计划中的实验将使用分子生物学、电生理学和钠成像技术。这一建议的目的是确定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靶点的病理条件，如当听觉过敏症门刻板运动自闭症 行为模式。加深我们对正常感觉编码的理解，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综合征和结节性硬化症具有深远的影响。此外，提高对这类独特通道的认识将很可能导致治疗干预，因为它们在缺氧和脑缺血中可能起到保护作用。此外，它们的药理活性将使它们成为控制癫痫发作活动的靶点。

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.