Open channel block of A-type, kv4.3, and delayed rectifier K+ channels, Kv1.3 and Kv3.1, by sibutramine.
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.
Kim
Sung Eun
SE
Department of Physiology, Medical Research Center, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, Korea.
Ahn
Hye Sook
HS
Choi
Bok Hee
BH
Jang
Hyun-Jong
HJ
Kim
Myung-Jun
MJ
Rhie
Duck-Joo
DJ
Yoon
Shin-Hee
SH
Jo
Yang-Hyeok
YH
Kim
Myung-Suk
MS
Sung
Ki-Wug
KW
Hahn
Sang June
SJ
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
D003503:Cyclobutanes; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D051672:Shal Potassium Channels; D051670:Shaw Potassium Channels; C058254:sibutramine