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Regulation of human cardiac Kv1.5 channels by extracellular acidification

  • Ion channels, receptors and transporters
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Abstract

Human Kv1.5 channels (hKv1.5) conduct the ultra-rapid delayed rectifier potassium current (I Kur), which plays an important role in action potential repolarization of atrial myocytes. The present study was undertaken to examine the effects of acidic pH on hKv1.5 wild-type (WT) and its pore mutant channels heterologously expressed in Chinese hamster ovary (CHO) cells using site-directed mutagenesis combined with whole-cell patch-clamp technique. Both extracellular and intracellular acidifications equally and reversely reduced the amplitude of hKv1.5 currents. The extracellular acidification significantly shifted the voltage dependence of current activation to more depolarized potentials and accelerated deactivation kinetics of the current. The ancillary β subunits Kvβ1.3 and Kvβ1.2, known to modify the pharmacological sensitivities of hKv1.5, enhanced the extracellular proton-induced inhibitory effect on hKv1.5 current. In addition, several mutants (T462C, T479A, T480A, and I508A) exhibited significantly higher sensitivity to acidic pH-induced inhibition compared with WT channel, whereas the inhibitory effect of acidic pH was markedly reduced in H463G mutant. These observations indicate that (1) extracellular acidification modifies hKv1.5 gating and activity, (2) β subunits and several residues (T462, T479, T480, and I508) play critical roles in determining the sensitivity of the channel to acidic exposure, and (3) H463 may be a critical sensor for the channel inhibition by extracellular protons.

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Acknowledgments

This study was supported by Grant-in-Aid for Scientific Research (No. 25460287 to Hiroshi Matsuura) from The Japan Society for the Promotion of Science.

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    Authors and Affiliations

    1. Department of Physiology, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan

      Shuang Wang, Wei-Guang Ding, Jia-Yu bai, Futoshi Toyoda & Hiroshi Matsuura

    2. Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China

      Shuang Wang & Min-Jie Wei

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    Correspondence to Min-Jie Wei or Hiroshi Matsuura.

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    Shuang Wang and Wei-Guang Ding contributed equally to this work.

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    Wang, S., Ding, WG., bai, JY. et al. Regulation of human cardiac Kv1.5 channels by extracellular acidification. Pflugers Arch - Eur J Physiol 468, 1885–1894 (2016). https://doi.org/10.1007/s00424-016-1890-x

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