Kv4.2 potassium channels play a critical role in postsynaptic excitability. Immunocytochemical studies reveal a somatodendritic Kv4.2 expression pattern, with the channels concentrated mainly at dendritic spines. The molecular mechanism that underlies the localization of Kv4.2 to this subcellular region is unknown. We used the yeast two-hybrid system to identify the Kv4.2-associated proteins that are involved in channel localization. Here we demonstrate a direct interaction between Kv4.2 and the actin-binding protein, filamin. We show that Kv4.2 and filamin can be coimmunoprecipitated both in vitro and in brain and that Kv4.2 and filamin share an overlapping expression pattern in the cerebellum and cultured hippocampal neurons. To examine the functional consequences of this interaction, we expressed Kv4.2 in filamin(+) and filamin(-) cells and performed immunocytochemical and electrophysiological analyses. Our results indicate that Kv4.2 colocalizes with filamin at filopodial roots in filamin(+) cells but shows a nonspecific expression pattern in filamin(-) cells, with no localization to filopodial roots. Furthermore, the magnitude of whole-cell Kv4.2 current density is approximately 2.7-fold larger in filamin(+) cells as compared with these currents in filamin(-) cells. We propose that filamin may function as a scaffold protein in the postsynaptic density, mediating a direct link between Kv4.2 and the actin cytoskeleton, and that this interaction is essential for the generation of appropriate Kv4.2 current densities.
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