N-type inactivation of voltage-gated K+ channels is conferred by the N-terminal “ball” domains of select pore-forming α subunits or of auxiliary β subunits, and influences electrical cellular excitability. Here, we show that hemin impairs inactivation of K+ channels formed by Kv3.4 α subunits as well as that induced by the subunits Kvβ1.1, Kvβ1.2, and Kvβ3.1 when coexpressed with α subunits of the Kv1 subfamily. In Kvβ1.1, 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 mechanismfor a dynamic regulation of Kv channel inactivation by heme/hemin in N-terminal ball domains of Kv α and auxiliary β subunits. Free intracellular heme therefore has the potential to regulate cellular excitability via modulation of Kv channel inactivation.
Coburger, I., Yang, K., Bernert, A. et al. Impact of intracellular hemin on N-type inactivation of voltage-gated K+ channels. Pflugers Arch - Eur J Physiol 472, 551–560 (2020). https://doi.org/10.1007/s00424-020-02386-1
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Pflügers Archiv - European Journal of Physiology