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Molecular determinants of the inhibition of human Kv1.5 potassium currents by external protons and Zn²⁺

Steven J. Kehl, Cyrus Eduljee, Daniel C. H. Kwan, Shetuan Zhang and David Fedida

Using human Kv1.5 channels expressed in HEK293 cells we assessed the ability of H to mimic the previously reported action of Zn²⁺ to inhibit macroscopic hKv1.5 currents, and using site-directed mutagenesis, we addressed the mechanistic basis for the inhibitory effects of H and Zn²⁺. As with Zn²⁺, H caused a concentration-dependent, K-sensitive and reversible reduction of the maximum conductance (g_max). With zero, 5 and 140 mM K the pK_H for this decrease of g_max was 6.8, 6.2 and 6.0, respectively. The concentration dependence of the block relief caused by increasing [K⁺]_o was well fitted by a non-competitive interaction between H and K_, for which the K_D for the K⁺ binding site was 0.5-1.0 mM. Additionally, gating current analysis in the non-conducting mutant hKv1.5 W472F showed that changing from pH 7.4 to pH 5.4 did not affect Q_max and that charge immobilization, presumed to be due to C-type inactivation, was preserved at pH 5.4. Inhibition of hKv1.5 currents by H or Zn²⁺ was substantially reduced by a mutation either in the channel turret (H463Q) or near the pore mouth (R487V). In light of the requirement for R487, the homologue of Shaker T449, as well as the block-relieving action of K, we propose that H⁺ or Zn²⁺ binding to histidine residues in the pore turret stabilizes a channel conformation that is most likely an inactivated state.

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