title: Coumarsabin hastens C-type inactivation gating of voltage-gated K⁺ channels.
abstract: During prolonged depolarization, voltage-gated K(+) (Kv) channels display C-type inactivation, a process which is due to selectivity filter destabilization and serves to limit K(+) flux. Here we reported that coumarsabin, a coumarin derivative isolated from Juniperus Sabina, could hasten C-type inactivation and thus cause block of Kv channels in neuronal NG108-15 cells and Kv1.2 channels heterologously expressed in lung epithelial H1355 cells. In NG108-15 cells, extracellular, but not intracellular, coumarsabin (30 μM) strongly speeded up Kv current decay and caused a left-shift in the steady-state inactivation curve. Coumarsabin inhibited end-of-pulse Kv currents with an IC50 of 13.4 μM. The kinetics and voltage-dependence of activation were not affected by coumarsabin. The degree of block by coumarsabin was not enhanced by a reduction in intracellular K(+) concentration. Data reveal that coumarsabin was a closed channel blocker and it displayed a frequency-independent mode of inhibition. Coumarsabin did not accelerate current decay in a Kv1.2 mutant (V370G) defective in C-type inactivation. Taken together, our data suggest that Kv channel inhibition by coumarsabin did not appear to result from a direct obstruction of the outer pore but relied on C-type inactivation.
authors: Graduate Institute of Acupuncture, China Medical University, Taichung 40402, Taiwan.
authors: Yi-Hung
authors: YH
authors: Chen
authors: King-Chuen
authors: KC
authors: Wu
authors: Chin-Tsang
authors: CT
authors: Yang
authors: Yuan-Kun
authors: YK
authors: Tu
authors: Chi-Li
authors: CL
authors: Gong
authors: Chia-Chia
authors: CC
authors: Chao
authors: Min-Fan
authors: MF
authors: Tsai
authors: Yue-Hsiung
authors: YH
authors: Kuo
authors: Yuk-Man
authors: YM
authors: Leung
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D056547:CA1 Region, Hippocampal / Q000166:cytology; D045744:Cell Line, Tumor; D003374:Coumarins / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects*; D018653:Juniperus; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018515:Plant Leaves; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D003374:Coumarins; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; C583714:coumarsabin