Subcellular Localization of Neuronal Ion Channels

University Of Southern California, Los Angeles CA

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Abstract

DESCRIPTION (provided by applicant): The long-term goal of this research is to understand the molecular mechanisms involved in intracellular transport and localization of voltage-gated potassium channels. Specifically, peptide motifs within the primary amino acid structure of potassium channels that specify localization to the axon or to the dendrite will be identified. The role of interacting proteins that are involved in localization of potassium channels will also be studied. Biolistic transfection will be used to express proteins in cultured brain slices, enabling their subcellular localization to be visualized in neurons in a wild-type environment. Chimeras composed of a potassium channel that localizes to the axon and another that localizes to the dendrite, as well as deletion mutants of each channel will be tested in this assay to map regions responsible for axonal and dendritic localization. The assay will also be used to study the role of interacting proteins in subcellular localization of K+ channels. The first aim of this proposal is to investigate mechanisms by which potassium channels are specifically localized to axonal and dendritic compartments of neurons. Aim 2 is to investigate the role in localization of proteins that are known to interact with potassium channels and to identify additional interacting proteins using the yeast two-hybrid method. The electrical properties of excitable cells are highly dependent on voltage-gated potassium channels. Potassium channels have been implicated in diseases associated with impaired control of excitability such as epilepsy. While the physiology of individual potassium channels is relatively well understood at the molecular level, the question of how a cell distributes these channels along its membrane to produce an overall pattern of electrical activity is not known. Understanding of how the cell regulates ionic currents by altering the subcellular distribution of ion channels could lead to novel avenues of pharmaceutical intervention in neurological diseases.