Role of KVS and MPS Subunits in Basic Neuronal Function

描述(由申请人提供)： 神经系统功能机制的破译是当前神经科学研究的一大热点。阐述神经系统微调以感知和响应特定刺激的细节对于理解感觉、信息整合和认知的机制至关重要。无脊椎动物模型系统为这一努力做出了重大贡献，因为基本神经功能的许多细节都被显着保守。对于线虫来说尤其如此，线虫的相对简单导致了对整个神经系统的发育、结构和功能的全面描述。最近，我们克隆并表达了一种电压门控性钾通道KVS，它在线虫神经系统中介导基本的神经元兴奋性。此外，我们还克隆了第一个线虫MIRP基因MPS-1。水貂相关多肽(MiRPs)是一种与K+通道结合以改变其功能的小跨膜蛋白。MPS-1与人类心脏MiRP1和MiRP3有显著的同源性(进一步强调了秀丽线虫作为模型系统理解我们自身生物学过程的重要性)，与感觉神经元中的KVS合作产生神经元性钾电流IK。最近发现的这种通道复合体提出了几个与遗传、生理和功能相关的问题。这项建议的主要目的是研究KVS和MPS-1的功能。本项目将阐明钾通道在决定线虫神经元兴奋性中的作用，并将加深我们对基本神经元过程的理解。我们的4个具体目标是：1目的：通过突变的种系基因失活产生KVS-1和MPS-1基因敲除蠕虫。2目的：研究KVS和MPS的加工、运输和亚细胞定位。3目的：研究KVS和MPS-1蛋白对两栖神经元基本功能的影响，探讨KVS和MPS-1蛋白在体外培养和体内化学感受神经元中的作用。4目的：建立线虫MiRPs超家族。

DESCRIPTION (provided by applicant): Deciphering mechanisms of nervous system function is a major focus of current neuroscience research. Elaborating the details by which the nervous system is fine-tuned to sense and respond to specific stimuli is of critical importance for understanding mechanisms of sensory perception, information integration and cognition. Invertebrate model systems are making a significant contribution to this effort since many details of basic neuronal function are remarkably conserved. This is particularly actual with the nematode C. elegans whose comparative simplicity invites a comprehensive description of the development, structure and function of the entire nervous system. Recently, we have cloned and expressed functionally a voltage-gated potassium channel, KVS that mediates basic neuronal excitability in C. elegans nervous system. In addition we cloned mps-1, the first C. elegans MiRP. MinK Related Peptides (MiRPs) are small transmembrane proteins that associate with K+ channels to alter their function. MPS- 1 which shares significant homology with cardiac human MiRP1 and MiRP3 (further underscoring the importance of C. elegans as model system to understand our own biological processes), partners with KVS in sensory neurons to produce the neuronal potassium current IK. The recent discovery of this channel complex poses several questions of genetic, physiological and functional relevance. The broad aim of this proposal is to study KVS and MPS-1 function. This project will elucidate the role of potassium channels in determining C. elegans neuronal excitability and will improve our understanding of basic neuronal processes. Our 4 specific aims are: 1 Aim: To generate kvs-1 and mps-1 knockout worms through mutational germline gene inactivation. 2 Aim: To investigate kvs and mps processing, trafficking and subcellular localization. 3 Aim: To characterize chemosensory neuron physiology in culture and in vivo and to define how KVS and MPS-1 proteins influence amphid neuron basic function. 4 Aim: To establish the superfamily of C. elegans MiRPs.