Localization and enhanced current density of the Kv4.2 potassium channel by interaction with the actin-binding protein filamin

Kv4.2 potassium channels play a critical role in postsynaptic excitability. Immunocytochemical studies reveal a somatodendritic Kv4.2 expression patte rn, with the channels concentrated mainly at dendritic spines. The molecula r mechanism that underlies the localization of Kv4.2 to this subcellular re gion is unknown. We used the yeast two-hybrid system to identify the Kv4.2- associated proteins that are involved in channel localization. Here we demo nstrate a direct interaction between Kv4.2 and the actin-binding protein, f ilamin. 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 expressi on pattern in the cerebellum and cultured hippocampal neurons. To examine t he functional consequences of this interaction, we expressed Kv4.2 in filam in(+) and filamin(-) cells and performed immunocytochemical and electrophys iological analyses. Our results indicate that Kv4.2 colocalizes with filami n at filopodial roots in filamin(+) cells but shows a nonspecific expressio n pattern in filamin(-) cells, with no localization to filopodial roots. Fu rthermore, the magnitude of whole-cell Kv4.2 current density is similar to2 .7-fold larger in filamin(+) cells as compared with these currents in filam in(-) cells. We propose that filamin may function as a scaffold protein in the postsynaptic density, mediating a direct link between Kv4.2 and the act in cytoskeleton, and that this interaction is essential for the generation of appropriate Kv4.2 current densities.