Direct Block of Cloned K+ Channels, Kv1.5 and Kv1.3, by Cyclosporin A, Independent of Calcineurin Inhibition
The Korean Journal of Physiology and Pharmacology
; : 353-361, 2005.
Article
in English
| WPRIM (Western Pacific)
| ID: wpr-728410
Responsible library:
WPRO
ABSTRACT
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 1.0microM. 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 7.0microM-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 1.1microM. 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.
Full text:
Available
Database:
WPRIM (Western Pacific)
Main subject:
Ovary
/
Brain
/
Cricetulus
/
Cyclosporine
/
Clone Cells
/
Patch-Clamp Techniques
/
Calcineurin
/
Inhibitory Concentration 50
/
Membranes
Limits:
Animals
Language:
English
Journal:
The Korean Journal of Physiology and Pharmacology
Year:
2005
Document type:
Article