The purpose of the studies proposed in this grant is to understand, in molecular terms, the mechanisms underlying the localization of ion channels to specific subcellular regions in neurons. Studies will concentrate on elucidating the mechanisms by which the voltage-gated K+ channels from the Kv4 and Kv1 families are localized to and within subcellular compartments in neurons.
The aims are as follows: 1. To investigate the mechanisms underlying dendritic localization of Kv1.3 in Purkinje cells of the cerebellum. 2. To define the role of adaptor proteins in the transport and regulation of expression of Kv4.2. 3. To use phage display antibodies to investigate the mechanisms underlying localization of Kv4.2 within the dendritic compartment of cortical and hippocampal pyramidal cells. 4. To identify proteins that interact with the dileucine motif of Kv4.2 and play a role in mediating dendritic targeting of the channel. The ultimate goal of this research is to understand how K+ channels are localized to specific subcellular regions in neurons. This is an important aspect of K+ channel regulation, derangements of which have been shown to lead to diseases such as epilepsy. K+ channel localization will also serve as a model to understand subcellular trafficking of proteins in general. Subcellular trafficking of proteins underlies many essential functions of neurons, such as learning and memory. In addition faulty protein trafficking has been linked to such neurological diseases as Alzheimer's disease and Huntington's disease. ? ?
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