title: Effects of haloperidol on Kv4.3 potassium channels.
abstract: Haloperidol is commonly used in clinical practice to treat acute and chronic psychosis, but it also has been associated with adverse cardiovascular events. We investigated the effects of haloperidol on Kv4.3 currents stably expressed in CHO cells using a whole-cell patch-clamp technique. Haloperidol did not significantly inhibit the peak amplitude of Kv4.3, but accelerated the decay rate of inactivation of Kv4.3 in a concentration-dependent manner. Thus, the effects of haloperidol on Kv4.3 were estimated from the integral of the Kv4.3 currents during the depolarization pulse. The Kv4.3 was decreased by haloperidol in a concentration-dependent manner with an IC50 value of 3.6 μM. Haloperidol accelerated the decay rate of Kv4.3 inactivation and activation kinetics in a concentration-dependent manner, thereby decreasing the time-to-peak. Haloperidol shifted the voltage dependence of the steady-state activation and inactivation of Kv4.3 in a hyperpolarizing direction. Haloperidol also caused an acceleration of the closed-state inactivation of Kv4.3. Haloperidol produced a use-dependent block of Kv4.3, which was accompanied by a slowing of recovery from the inactivation of Kv4.3. These results suggest that haloperidol blocks Kv4.3 by both interacting with the open state of Kv4.3 channels during depolarization and accelerating the closed-state inactivation at subthreshold membrane potentials.
authors.affiliation: Department of Pharmacology, Cell Death and Disease Research Center, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, , Seoul 137-701, Republic of Korea.
authors.forename: Hong Joon
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Cell Death and Disease Research Center, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, , Seoul 137-701, Republic of Korea. Electronic address: sungkw@catholic.ac.kr.
authors.forename: Ki-Wug
authors.initials: KW
authors.lastname: Sung
authors.affiliation: Department of Physiology, Cell Death and Disease Research Center, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, 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; D003412:Cricetulus; D006220:Haloperidol / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D051672:Shal Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology
chemical_list: D014150:Antipsychotic Agents; D026902:Potassium Channel Blockers; D051672:Shal Potassium Channels; D006220:Haloperidol
keywords: Closed-state inactivation; Haloperidol; Kv4.3; Open-channel block