Dependence of 6β-acetoxy-7α-hydroxyroyleanone block of Kv1.2 channels on C-type inactivation |
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| Authors: | Yuk-Man Leung Kar-Lok Wong Chia-Huei Lin Chia-Chia Chao Chun-Hsiao Chou Li-Yun Chang Siao-Wei Chen Tzu-Hurng Cheng Yueh-Hsiung Kuo |
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| Institution: | (1) Graduate Institute of Neural and Cognitive Sciences, China Medical University, Taichung, 40402, Taiwan;(2) Department of Anesthesia, China Medical University and Hospital, Taichung, 40402, Taiwan;(3) Graduate Institute of Molecular Systems Biomedicine, China Medical University, Taichung, 40402, Taiwan;(4) Department of Biological Science and Technology, China Medical University, Taichung, 40402, Taiwan;(5) Tsuzuki Institute for Traditional Medicine, China Medical University, Taichung, 40402, Taiwan |
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| Abstract: | Voltage-gated K+ (Kv) channels exhibit slow or C-type inactivation during continuous depolarization. A selective pharmacological agent targeting
C-type inactivation is hitherto lacking. Here, we report that 6β-acetoxy-7α-hydroxyroyleanone (AHR), a diterpenoid compound
isolated from Taiwania cryptomerioides, can selectively modify C-type inactivation of Kv1.2 channels. Extracellular, but not intracellular, AHR (50 μM) dramatically
accelerated the slow decay of Kv currents and left-shifted the steady-state inactivation curve. AHR blocked Kv currents with
an IC50 of 17.7 μM. AHR did not affect the kinetics and voltage-dependence of Kv1.2 channel activation. Channel block by AHR was
independent of intracellular K+ concentration. In addition, effect of AHR was much attenuated in a Kv1.2 V370G mutant defective in C-type inactivation. Therefore,
block of Kv1.2 channels by AHR did not appear to involve direct occlusion of the outer pore but depended on C-type inactivation.
AHR could thus be a probe targeting Kv channel C-type inactivation gate. |
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