Dependence of 6beta-acetoxy-7alpha-hydroxyroyleanone block of Kv1.2 channels on C-type inactivation.
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 6beta-acetoxy-7alpha-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 muM) dramatically accelerated the slow decay of Kv currents and left-shifted the steady-state inactivation curve. AHR blocked Kv currents with an IC(50) of 17.7 muM. 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.
Leung
Yuk-Man
YM
Graduate Institute of Neural and Cognitive Sciences, China Medical University, Taichung, 40402, Taiwan. ymleung@mail.cmu.edu.tw
Wong
Kar-Lok
KL
Lin
Chia-Huei
CH
Chao
Chia-Chia
CC
Chou
Chun-Hsiao
CH
Chang
Li-Yun
LY
Chen
Siao-Wei
SW
Cheng
Tzu-Hurng
TH
Kuo
Yueh-Hsiung
YH
D019943:Amino Acid Substitution; D002460:Cell Line; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D055724:Electrophysiological Phenomena / Q000187:drug effects; D006801:Humans; D051663:Kv1.2 Potassium Channel / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*
C469378:7-acyloxy-6-hydroxyroyleanone; D004224:Diterpenes; D051663:Kv1.2 Potassium Channel; D026902:Potassium Channel Blockers