Constitutive inactivation of the hKv1.5 mutant channel, H463G, in K+-free solutions at physiological pH |
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Authors: | Shetuan Zhang Cyrus Eduljee Daniel C H Kwan Steven J Kehl David Fedida |
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Institution: | (1) Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, University of Manitoba, 351 Tache Avenue, R2H 2A6 Winnipeg, Manitoba, Canada;(2) Department of Physiology, University of British Columbia, 2146 Health Sciences Mall, V6T 1Z3 Vancouver, British Columbia, Canada |
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Abstract: | Extracellular acidification and reduction of extracellular K+ are known to decrease the currents of some voltage-gated potassium channels. Although the macroscopic conductance of WT hKv1.5 channels is not very sensitive to K+]o at pH 7.4, it is very sensitive to K+]o at pH 6.4, and in the mutant, H463G, the removal of K+
o virtually eliminates the current at pH 7.4. We investigated the mechanism of current regulation by K+
o in the Kv1.5 H463G mutant channel at pH 7.4 and the wild-type channel at pH 6.4 by taking advantage of Na+ permeation through inactivated channels. Although the H463G currents were abolished in zero K+]o, robust Na+ tail currents through inactivated channels were observed. The appearnnce of H463G Na+ currents with a slow rising phase on repolarization after a very brief depolarization (2 ms) suggests that channels could
activate directly from closed-inactivated states. In wild-type channels, when intracellular K+ was replaced by NMG+ and the inward Na+ current was recorded, addition of 1 mM K+ prevented inactivation, but changing pH from 7.4 to 6.4 reversed this action. The data support the idea that C-type inactivation
mediated at R487 in Kv1.5 channels is influenced by H463 in the outer pore. We conclude that both acidification and reduction
of K+]o inhibit Kv1.5 channels through a common mechananism (i.e., by increasing channel inactivation, which occurs in the resting
state or develops very rapidly after activation). |
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Keywords: | Voltage-gated K+ channels inactivation protons extracellular potassium concentration |
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