HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 292/5/C1714    most recent 00258.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Ahn, H. S. Articles by Hahn, S. J. Search for Related Content PubMed PubMed Citation Articles by Ahn, H. S. Articles by Hahn, S. J.

RECEPTORS AND SIGNAL TRANSDUCTION

Calcineurin-independent inhibition of K_V1.3 by FK-506 (tacrolimus): a novel pharmacological property

¹Department of Physiology, ²Department of Pharmacology, and ³Department of Biochemistry, Medical Research Center, College of Medicine, Catholic University of Korea, Socho-gu, Seoul; and ⁴Department 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_V1.3, stably expressed in Chinese hamster ovary cells, was investigated with the whole cell patch-clamp technique. FK-506 inhibited K_V1.3 in a reversible, concentration-dependent manner with an IC₅₀ of 5.6 µM. Rapamycin, another immunosuppressant, produced effects that were similar to those of FK-506 (IC₅₀ = 6.7 µM). Other calcineurin inhibitors (cypermethrin or calcineurin autoinhibitory peptide) alone had no effect on the amplitude or kinetics of K_V1.3. 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_V1.3. FK-506 shifted the steady-state inactivation curves of K_V1.3 in the hyperpolarizing direction in a concentration-dependent manner. The apparent dissociation constant for FK-506 to inhibit K_V1.3 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_V1.3 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_V1.5 and K_V4.3 in a concentration-dependent manner with IC₅₀ of 4.6 and 53.9 µM, respectively. The present results indicate that FK-506 inhibits K_V1.3 directly and that this effect is not mediated via the inhibition of the phosphatase activity of calcineurin.

potassium channel; immunosuppressant; calcineurin inhibitor