Role of KVS and MPS Subunits in Basic Neuronal Function

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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. etegans 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 raps-l, 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 raps-1 knockout worms through mutational germline gene inactivation. 2 Aim: To investigate kvs and raps processing, trafficking and subceUular 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 ofC. elegans MiRPs