| 17166943 |
Ahn HS, Kim SE, Choi BH, Choi JS, Kim MJ, Rhie DJ, Yoon SH, Jo YH, Kim MS, Sung KW, Kwon OJ, Hahn SJ: Calcineurin-independent inhibition of KV1.3 by FK-506 (tacrolimus): a novel pharmacological property. Am J Physiol Cell Physiol. 2007 May;292(5):C1714-22. Epub 2006 Dec 13.
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 microM. Rapamycin, another immunosuppressant, produced effects that were similar to those of FK-506 (IC (50) = 6.7 microM). 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 microM. 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 microM, 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. |
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