Molecular Properties of Mammalian Neuronal Dendritic K+ Channels

University Of Texas At Austin, Austin TX

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Abstract

Our general working hypothesis is that the functional properties of native voltage-gated potassium channels arise through the interactions of different auxiliary proteins with the core pore forming alpha subunits. This hypothesis emphasizes the importance of protein-protein interactions in the formation, trafficking, and regulation of neuronal electrical properties. In this proposal we will be testing the specific hypothesis that Kv4 alpha subunits, also called Shal type Kv channels, assemble with auxiliary KChlP proteins and DPP proteins to form a macromolecular protein complex that is trafficked to the dendrites in CA1 pyramidal neurons to form a functionally important A current channel. Our studies will focus on the analysis of changes in A current function in native neurons in response to molecular genetic manipulations in expression level for different subunits in native neurons. Next, we will examine the functional effects of introducing mutant version of the important subunits proteins that either lack the ability to perform specific protein-protein interactions or are unable to be modified by particular post-translational modifications. By characterizing the changes in function at several different levels, we will determine the specific roles of different subunit proteins, functional motifs, and post-translational modifications in forming the A current phenotypes of CA1 pyramidal neurons. These studies will have a general impact on our understanding of the molecular control of neuronal electrical phenotypes as well as the approaches we will take in understand the functional importance of other ion channels and auxiliary subunit proteins. Our studies will have a general impact on our understanding of the regulation of excitability that will impact many areas of health related research including epilepsy, heart disease, asthma, and AIzheimer's.