Open channel block of Kv1.3 by rosiglitazone and troglitazone: Kv1.3 as the pharmacological target for rosiglitazone.
The effects of rosiglitazone and troglitazone were examined on cloned Kv1.3 channels stably expressed in Chinese hamster ovary cells using the whole-cell configuration of the patch-clamp technique. Rosiglitazone decreased the Kv1.3 currents and accelerated the decay rate of current inactivation in a concentration-dependent manner with an IC(50) of 18.6 microM. These effects were reversible after washout of the drug. Troglitazone caused the block of Kv1.3 with a similar pattern but was five times more potent than rosiglitazone with an IC(50) of 3.5 microM. The block of Kv1.3 by rosiglitazone and troglitazone was voltage-dependent at a membrane potential coinciding with the activation of the channels. Both drugs decreased the tail current amplitude and slowed the deactivation process of Kv1.3, resulting in a tail crossover phenomenon. These results indicate that rosiglitazone and troglitazone block the open state of Kv1.3 channels, suggesting that it is an important pharmacological target for rosiglitazone as a potent blocker of Kv1.3 channels.
Ahn
Hye Sook
HS
Department of Physiology, Medical Research Center, College of Medicine, The Catholic University of Korea, 505 Banpo-Dong, Socho-Gu, Seoul, South Korea.
Kim
Sung Eun
SE
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
Kim
Seong Yun
SY
Hahn
Sang June
SJ
D000818:Animals; D016466:CHO Cells; D002839:Chromans / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D014665:Vasodilator Agents / Q000494:pharmacology
D002839:Chromans; D051664:Kv1.3 Potassium Channel; D045162:Thiazolidinediones; D014665:Vasodilator Agents; D000077154:Rosiglitazone; D000077288:Troglitazone