Impact of intracellular hemin on N-type inactivation of voltage-gated K+ channels

Abstract

N-type inactivation of voltage-gated K+ channels is conferred by the N-terminal "ball" domains of select pore-forming alpha subunits or of auxiliary beta subunits, and influences electrical cellular excitability. Here, we show that hemin impairs inactivation of K+ channels formed by Kv3.4 alpha subunits as well as that induced by the subunits Kv beta 1.1, Kv beta 1.2, and Kv beta 3.1 when coexpressed with alpha subunits of the Kv1 subfamily. In Kv beta 1.1, hemin interacts with cysteine and histidine residues in the N terminus (C7 and H10) with high affinity (EC50 100 nM). Similarly, rapid inactivation of Kv4.2 channels induced by the dipeptidyl peptidase-like protein DPP6a is also sensitive to hemin, and the DPP6a mutation C13S eliminates this dependence. The results suggest a common mechanism for a dynamic regulation of Kv channel inactivation by heme/hemin in N-terminal ball domains of Kv alpha and auxiliary beta subunits. Free intracellular heme therefore has the potential to regulate cellular excitability via modulation of Kv channel inactivation.