KChIP2 modulates the cell surface expression of Kv1.5-encoded K⁺ channels

The Kv channel interacting proteins (KChIPs) were identified in a yeast two hybrid screen using the N terminus of Kv4.3 as bait. Previous studies have demonstrated that KChIP2 associates with voltage-gated K⁺ (Kv) pore-forming (α) subunits of the Kv4 subfamily and contributes to the formation of the rapidly inactivating and recovering Kv4-encoded cardiac transient outward K⁺ channels, I_to,f. Here, we report that co-expression of KChIP2 (or KChIP1) also modulates the functional cell surface expression of Kv1.5-encoded K⁺ channels in transiently transfected HEK-293 cells. In contrast to the effects of KChIP2 on Kv4 channels, however, co-expression of KChIP2 (or KChIP1) decreases Kv1.5-encoded K⁺ currents. Although current densities are reduced, KChIP2 (or KChIP1) co-expression does not affect the time- or voltage-dependent properties of heterologously expressed Kv1.5-encoded K⁺ currents. Immunohistochemical and cell surface biotinylation experiments demonstrate that KChIP2 reduces the cell surface expression of Kv1.5, likely by inhibiting forward trafficking from the endoplasmic reticulum. In addition, biochemical experiments reveal that KChIP2 co-immunoprecipitates with Kv1.5 (as well as Kv4.2/Kv4.3) from adult mouse ventricles, demonstrating that, similar to other Kv accessory subunits, KChIP2 is a multifunctional Kv channel accessory subunit. Taken together, the results here suggest that KChIP2 contributes to the formation of functional mouse ventricular (Kv1.5-encoded) I_K,slow1 channels as well, perhaps, as other Kv1.5-encoded K⁺ currents, including I_Kur (I_K,ultrarapid), in human atria.