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First published online on March 28, 2002.
 Copyright © 2002 by The Physiological Society
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Received November 22, 2001
Accepted after revision February 19, 2002

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

S J. Kehl1*, Cyrus Eduljee1, Daniel C.H. Kwan1, Shetuan Zhang1, and David Fedida1

1 Department of Physiology, University of British Columbia, 2146 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3

* To whom correspondence should be addressed. E-mail: skehl{at}interchange.ubc.ca.

Using human Kv1.5 channels expressed in HEK293 cells we assessed the ability of H+o 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+o and Zn2+. As with Zn2+, H+o caused a concentration-dependent, K+o-sensitive and reversible reduction of the maximum conductance (gmax). With zero, 5 and 140 mM K+o the pKH for this decrease of gmax 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+o and K+o, for which the KD for the K+ binding site was 0.5-1.0 mM. It is unlikely that an accumulation of inactivation accounts for the decline of gmax since it was not affected by decreasing the stimulus frequency. 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 Qmax 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+o 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+o, 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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