title: Block of Kv4.3 potassium channel by trifluoperazine independent of CaMKII.
abstract: Trifluoperazine, a trifluoro-methyl phenothiazine derivative, is widely used in the management of schizophrenia and related psychotic disorders. We studied the effects of trifluoperazine on Kv4.3 currents expressed in CHO cells using the whole-cell patch-clamp technique. Trifluoperazine blocked Kv4.3 in a concentration-dependent manner with an IC50 value of 8.0±0.4 μM and a Hill coefficient of 2.1±0.1. Trifluoperazine also accelerated the inactivation and activation (time-to-peak) kinetics in a concentration-dependent manner. The effects of trifluoperazine on Kv4.3 were completely reversible after washout. The effects of trifluoperazine were not affected by the pretreatment of KN93, which is another CaMKII inhibitor. In addition, the inclusion of CaMKII inhibitory peptide 281-309 in the pipette solution did not modify the effect of trifluoperazine on Kv4.3. Trifluoperazine shifted the activation curve of Kv4.3 in a hyperpolarizing direction but did not affect the slope factor. The block of Kv4.3 by trifluoperazine was voltage-dependent with a steep increase across the voltage range of channel activation. Voltage dependence was also observed over the full range of activation (δ=0.18). Trifluoperazine slowed the time course for recovery from inactivation of Kv4.3. Our results indicated that trifluoperazine blocked Kv4.3 by preferentially binding to the open state of the channel. This effect was not mediated via the inhibition of CaMKII activity.
authors.affiliation: Department of Physiology, Cell Death and Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors.forename: Yun Ju
authors.initials: YJ
authors.lastname: Chae
authors.affiliation: Department of Pharmacology, Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Jeonbuk 561-180, Republic of Korea.
authors.forename: Bok Hee
authors.initials: BH
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Integrated Research Institute of Pharmaceutical, The Catholic University of Korea, 43-1 Yeokgok 2-dong, Wonmi-gu, Bucheon, Gyeonggi-do, Republic of Korea.
authors.forename: Jin-Sung
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Department of Physiology, Cell Death and Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea. Electronic address: sjhahn@catholic.ac.kr.
authors.forename: Sang June
authors.initials: SJ
authors.lastname: Hahn
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D016466:CHO Cells; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003412:Cricetulus; D008564:Membrane Potentials / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D051672:Shal Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014268:Trifluoperazine / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D026902:Potassium Channel Blockers; D051672:Shal Potassium Channels; D014268:Trifluoperazine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: CaMKII inhibitors; Kv4.3; Trifluoperazine