Direct Block of Cloned K⁢ Channels, Kv1.5 and Kv1.3, by Cyclosporin A, Independent of Calcineurin Inhibition

• 영문명: Direct Block of Cloned K^⁢ Channels, Kv1.5 and Kv1.3, by Cyclosporin A, Independent of Calcineurin Inhibition
• 발행기관: 대한생리학회-대한약리학회
• 저자명: Bok Hee Choi Sang June Hahn
• 간행물 정보: 『The Korean Journal of Physiology & Pharmacology』제9권 제6호, 353~362쪽, 전체 10쪽
• 주제분류: 의약학 > 의학일반
• 파일형태: PDF
• 발행일자: 2005.01.01

영문 초록

The interaction of cyclosporine A (CsA), an immunosuppressant, with rat brain Kv1.5 (Kv1.5) channels, which were stably expressed in Chinese hamster ovary cells, was investigated using the whole-cell patch-clamp technique. CsA reversibly blocked Kv1.5 currents at ⁢50 mV in a reversible concentration- dependent manner with an apparent IC₅₀ of 1.0μM. Other calcineurin inhibitors (cypermethrin, autoinhibitory peptide) had no effect on Kv1.5 and did not prevent the inhibitory effect of CsA. Fast application of CsA led to a rapid and reversible block of Kv1.5, and the onset time constants of the CsA-induced block were decreased in a concentration-dependent manner. The CsA-induced block of Kv1.5 channels was voltage-dependent, with a steep increase over the voltage range of channel opening. However, the block exhibited voltage independence over the voltage range in which channels were fully activated. The rate constants for association and dissociation of CsA were 7.0μM^⁣1s^⁣1 and 8.1 s^⁣1, respectively. CsA slowed the deactivation time course, resulting in a tail crossover phenomenon. Block of Kv1.5 by CsA was use-dependent. CsA also blocked Kv1.3 currents at ⁢50 mV in a reversible concentration-dependent manner with an apparent IC₅₀ of 1.1μM. The same effects of CsA on Kv1.3 were also observed in excised inside-out patches when applied to the internal surface of the membrane. The present results suggest that CsA acts directly on Kv1.5 currents as an open-channel blocker, independently of the effects of CsA on calcineurin activity.

키워드

Cyclosporine A Kv1.5 Kv1.3 Calcineurin inhibitor Open channel block