title: Regulation of human cardiac Kv1.5 channels by extracellular acidification.
abstract: Human Kv1.5 channels (hKv1.5) conduct the ultra-rapid delayed rectifier potassium current (IKur), 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.
authors: Department of Physiology, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.|Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.
authors: Shuang
authors: S
authors: Wang
authors: Department of Physiology, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.
authors: Wei-Guang
authors: WG
authors: Ding
authors: Department of Physiology, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.
authors: Jia-Yu
authors: JY
authors: Bai
authors: Department of Physiology, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.
authors: Futoshi
authors: F
authors: Toyoda
authors: Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China. weiminjiecmu@163.com.
authors: Min-Jie
authors: MJ
authors: Wei
authors: Department of Physiology, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan. matuurah@belle.shiga-med.ac.jp.
authors: Hiroshi
authors: H
authors: Matsuura
mesh_terms: D000200:Action Potentials; D019943:Amino Acid Substitution; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating; D051666:Kv1.5 Potassium Channel / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011522:Protons
chemical_list: C496981:KCNA5 protein, human; D051666:Kv1.5 Potassium Channel; D011522:Protons
keywords: Acidification; Kv1.5; Low pH; Proton; Site-directed mutagenesis