Conserved Kv4 N-terminal domain critical for effects of Kv channel-interacting protein 2.2 on channel expression and gating

Association of Kv channel-interacting proteins (KChIPs) with Kv4 channels l eads to modulation of these A-type potassium channels (An, W, F,, Bowlby, M , R, Petty, M., Cao, J,, Ling, RP,, Mendoza, G., Hinson, J, W., Mattsson, R . I., Strassle, B, ni., Trimmer, J, S., and Rhodes, K. J, (2000) Nature 403 , 553-556), We cloned a KChIP2 splice variant (KChIP2.2) from human ventric le. In comparison with RChIP2.1, coexpression of KChIP2.2 with human Kv4 ch annels in mammalian cells slowed the onset of Kv4 current inactivation (23- fold), accelerated the recovery from inactivation (5-7-fold), and shifted K v4 steady-state inactivation curves by 8-29 mV to more positive potentials. The features of Kv4.2/KChIP2.2 currents closely resemble those of cardiac rapidly inactivating transient outward currents, KChIP2.2 stimulated the Kv 4 current density in Chinese hamster ovary cells by similar to 55-fold. Thi s correlated with a redistribution of immunoreactivity hom perinuclear area s to the plasma membrane. Increased Kv4 cell-surface expression and current density were also obtained in the absence of KChIP2.2 when the highly cons erved proximal Kv4 N terminus was deleted. The same domain is required for association of RChIP2.2 with Kv4 alpha -subunits. We propose that an effici ent transport of Kv4 channels to the cell surface depends on KChIP binding to the Kv4 N-terminal domain. Our data suggest that the binding is necessar y, but not sufficient, for the functional activity of KChIPs.