EXCEED THE SPACE PROVIDED. Voltage-gated K+ channels, or Kv channels,are fundamental components of electrical activity. As small changes in surface expression levels, localization and function of Kv channels can have dramatic effect on neuronal activity patterns, it is expected that neurons have evolved diverse mechanisms to precisely regulate these phenomena. This proposal is aimed at determining the fundamental mechanisms that specify the abundance, distribution and function of neuronalKv channels. We will focus our studies on the Shaker or Kvl subfamily of Kv channels, whose members co-assemble to form heteromeric channels expressed on axons and presynaptic terminals. This proposal is aimed at determining the role of specific protein-protein interactions that occur between component subunits of Kvl channel complexes, and between the channel complexes and Kvl channel Coordinating Proteins, or KCOPs. We will determine the signals that specify the differential intracellular trafficking and surface expression characteristics of Kvl channels, and the mechanism whereby known interacting proteins such as MAGUKs affect trafficking/expression of Kv channels. We will purify, clone and characterize novel proteins that specifiy juxtaparanodal Kvl channel localization and function in myelinated axons. As regulation of Kv channel activity influences action potential duration, amplitude and frequency, and synaptic efficacy, understanding the mechanisms controlling the composition of Kv channel complexes at the molecular level, anticipated from our proposed studies, will provide insights into the normal and abnormal function of neurons. It will thus contribute to the eventual understandingand treating of a variety of neurological disorders, including demyelinating disorders such as multiple sclerosis and spinal cord injury, and diseases associated with altered neuronal excitability such as genetic and acquired epilepsy, cognitive disorders, and affective disorders. PERFORMANCE SITE ========================================Section End===========================================
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