Open channel block of Kv1.3 by rosiglitazone and troglitazone: Kv1.3 as the pharmacological target for rosiglitazone
Open channel block of Kv1.3 by rosiglitazone and troglitazone: Kv1.3 as the pharmacological target for rosiglitazone
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DOI：
10.1007/s00210-006-0118-6
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发表时间：
2007-01-01
影响因子：
3.6
通讯作者：
Hahn, Sang June
中科院分区：
文献类型：
--
作者：
Ahn, Hye Sook;Kim, Sung Eun;Hahn, Sang June
采用膜片钳全细胞结构技术，研究了罗格列酮和曲格列酮对中国仓鼠卵巢细胞稳定表达的克隆Kv1.3通道的影响。罗格列酮降低了Kv1.3电流，并以浓度依赖性的方式加速了电流失活的衰减速率，IC50为18.6 μ m，这些作用在药物洗脱后是可逆的。罗格列酮和曲格列酮对Kv1.3的阻断作用与罗格列酮相似，但比罗格列酮强5倍，IC50为3.5 μ m。罗格列酮和曲格列酮对Kv1.3的阻断作用在与通道激活相一致的膜电位上具有电压依赖性。两种药物均降低尾电流幅值，减缓Kv1.3失活过程，导致尾交叉现象。这些结果表明，罗格列酮和曲格列酮阻断了Kv1.3通道的开放状态，提示它是罗格列酮作为Kv1.3通道的有效阻滞剂的重要药理靶点。
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 IC50 of 18.6 mu M. 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 IC50 of 3.5 mu M. 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.