Kv4.2 is the major voltage-gated K+ (Kv) channel R subunit responsible for the somatodendritic transient or A-type current ISA that activates at subthreshold membrane potentials. Stable association of Kv4.2 with diverse auxiliary subunits and reversible Kv4.2 phosphorylation regulate ISA function. Two classes of auxiliary subunits play distinct roles in modulating the biophysical properties of Kv4.2: dipeptidylpeptidase-like type II transmembrane proteins typified by DPPX-S, and cytoplasmic Ca2+ binding proteins known as K+ channel interacting proteins (KChIPs). Here, we characterize the convergent roles that DPPX-S and KChIPs play as component subunits of Kv4.2 channel complexes. We coexpressed DPPX-S with Kv4.2 in heterologous cells and found a dramatic redistribution of Kv4.2, releasing it from intracellular retention and allowing plasma membrane expression, as well as altered Kv4.2 phosphorylation, detergent solubility, and stability. These changes are remarkably similar to those obtained upon coexpression of Kv4.2 with the structurally distinct KChIPs1-3 auxiliary subunits. KChIP4a, which negatively affects the impact of other KChIPs on Kv4.2, also inhibits the effects of DPPX-S, consistent with the formation of a ternary complex of Kv4.2, DPPX-S, and KChIPs early in channel biosynthesis. Tandem MS analyses reveal that coexpression with DPPX-S or KChIP2 leads to a pattern of Kv4.2 phosphorylation in heterologous cells similar to that observed in brain, but lacking in cells expressing Kv4.2 alone. In conclusion, transmembrane DPPX-S and cytoplasmic KChIPs, despite having distinct structures and binding sites on Kv4.2, exert similar effects on Kv4.2 trafficking, but distinct effects on Kv4.2 gating.
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