Calcineurin-independent inhibition of KV1.3 by FK-506 (tacrolimus): a novel pharmacological property

1 Department of Physiology, 2 Department of Pharmacology, and 3 Department of Biochemistry, Medical Research Center, College of Medicine, Catholic University of Korea, Socho-gu, Seoul; and 4 Department of Pharmacology, Chonbuk National University, Jeonju, Korea Submitted 11 May 2006 ; accepted in fi...

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Published in:American Journal of Physiology: Cell Physiology 2007-05, Vol.292 (5), p.C1714-C1722
Main Authors: Ahn, Hye Sook, Kim, Sung Eun, Choi, Bok Hee, Choi, Jin-Sung, Kim, Myung-Jun, Rhie, Duck-Joo, Yoon, Shin Hee, Jo, Yang-Hyeok, Kim, Myung-Suk, Sung, Ki-Wug, Kwon, Oh-Joo, Hahn, Sang June
Format: Article
Language:English
Subjects:
Animals
Calcineurin - metabolism
Calcineurin Inhibitors
CHO Cells
Cricetinae
Cricetulus
Dose-Response Relationship, Drug
Immunosuppressive Agents - pharmacology
Kinetics
Kv1.3 Potassium Channel - antagonists & inhibitors
Kv1.3 Potassium Channel - genetics
Kv1.3 Potassium Channel - metabolism
Kv1.5 Potassium Channel - antagonists & inhibitors
Membrane Potentials - drug effects
Patch-Clamp Techniques
Potassium Channel Blockers - pharmacology
Pyrethrins - pharmacology
Shal Potassium Channels - antagonists & inhibitors
Sirolimus - pharmacology
Tacrolimus - pharmacology
Transfection
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Summary:1 Department of Physiology, 2 Department of Pharmacology, and 3 Department of Biochemistry, Medical Research Center, College of Medicine, Catholic University of Korea, Socho-gu, Seoul; and 4 Department of Pharmacology, Chonbuk National University, Jeonju, Korea Submitted 11 May 2006 ; accepted in final form 11 December 2006 The interaction of FK-506 with K V 1.3, stably expressed in Chinese hamster ovary cells, was investigated with the whole cell patch-clamp technique. FK-506 inhibited K V 1.3 in a reversible, concentration-dependent manner with an IC 50 of 5.6 µM. Rapamycin, another immunosuppressant, produced effects that were similar to those of FK-506 (IC 50 = 6.7 µM). Other calcineurin inhibitors (cypermethrin or calcineurin autoinhibitory peptide) alone had no effect on the amplitude or kinetics of K V 1.3. In addition, the inhibitory action of FK-506 continued, even after the inhibition of calcineurin activity. The inhibition produced by FK-506 was voltage dependent, increasing in the voltage range for channel activation. At potentials positive to 0 mV (where maximal conductance is reached), however, no voltage-dependent inhibition was found. FK-506 exhibited a strong use-dependent inhibition of K V 1.3. FK-506 shifted the steady-state inactivation curves of K V 1.3 in the hyperpolarizing direction in a concentration-dependent manner. The apparent dissociation constant for FK-506 to inhibit K V 1.3 in the inactivated state was estimated from the concentration-dependent shift in the steady-state inactivation curve and was calculated to be 0.37 µM. Moreover, the rate of recovery from inactivation of K V 1.3 was decreased. In inside-out patches, FK-506 not only reduced the current amplitude but also accelerated the rate of inactivation during depolarization. FK-506 also inhibited K V 1.5 and K V 4.3 in a concentration-dependent manner with IC 50 of 4.6 and 53.9 µM, respectively. The present results indicate that FK-506 inhibits K V 1.3 directly and that this effect is not mediated via the inhibition of the phosphatase activity of calcineurin. potassium channel; immunosuppressant; calcineurin inhibitor Address for reprint requests and other correspondence: S. J. Hahn, Dept. of Physiology, Coll. of Medicine, Catholic Univ. of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, Korea (e-mail: sjhahn{at}catholic.ac.kr )
ISSN:0363-6143
1522-1563
DOI:10.1152/ajpcell.00258.2006