title: Open channel block of A-type, kv4.3, and delayed rectifier K+ channels, Kv1.3 and Kv3.1, by sibutramine.
abstract: The effects of sibutramine on voltage-gated K+ channel (Kv)4.3, Kv1.3, and Kv3.1, stably expressed in Chinese hamster ovary cells, were investigated using the whole-cell patch-clamp technique. Sibutramine did not significantly decrease the peak Kv4.3 currents, but it accelerated the rate of decay of current inactivation in a concentration-dependent manner. This phenomenon was effectively characterized by integrating the total current over the duration of a depolarizing pulse to +40 mV. The IC50 value for the sibutramine block of Kv4.3 was 17.3 microM. Under control conditions, the inactivation of Kv4.3 currents could be fit to a biexponential function, and the time constants for the fast and slow components were significantly decreased after the application of sibutramine. The association (k+1) and dissociation (k-1) rate constants for the sibutramine block of Kv 4.3 were 1.51 microM-1s-1 and 27.35 s-1, respectively. The theoretical KD value, derived from k-1/k+1, yielded a value of 18.11 microM. The block of Kv4.3 by sibutramine displayed a weak voltage dependence, increasing at more positive potentials, and it was use-dependent at 2 Hz. Sibutramine did not affect the time course for the deactivating tail currents. Neither steady-state activation and inactivation nor the recovery from inactivation was affected by sibutramine. Sibutramine caused the concentration-dependent block of the Kv1.3 and Kv3.1 currents with an IC50 value of 3.7 and 32.7 microM, respectively. In addition, sibutramine reduced the tail current amplitude and slowed the deactivation of the tail currents of Kv1.3 and Kv3.1, resulting in a crossover phenomenon. These results indicate that sibutramine acts on Kv4.3, Kv1.3, and Kv3.1 as an open channel blocker.
authors.affiliation: Department of Physiology, Medical Research Center, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, Korea.
authors.forename: Sung Eun
authors.initials: SE
authors.lastname: Kim
authors.forename: Hye Sook
authors.initials: HS
authors.lastname: Ahn
authors.forename: Bok Hee
authors.initials: BH
authors.lastname: Choi
authors.forename: Hyun-Jong
authors.initials: HJ
authors.lastname: Jang
authors.forename: Myung-Jun
authors.initials: MJ
authors.lastname: Kim
authors.forename: Duck-Joo
authors.initials: DJ
authors.lastname: Rhie
authors.forename: Shin-Hee
authors.initials: SH
authors.lastname: Yoon
authors.forename: Yang-Hyeok
authors.initials: YH
authors.lastname: Jo
authors.forename: Myung-Suk
authors.initials: MS
authors.lastname: Kim
authors.forename: Ki-Wug
authors.initials: KW
authors.lastname: Sung
authors.forename: Sang June
authors.initials: SJ
authors.lastname: Hahn
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003503:Cyclobutanes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D051672:Shal Potassium Channels / Q000037:antagonists & inhibitors*; D051670:Shaw Potassium Channels / Q000037:antagonists & inhibitors*; D013997:Time Factors
chemical_list: D003503:Cyclobutanes; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D051672:Shal Potassium Channels; D051670:Shaw Potassium Channels; C058254:sibutramine