Effect of t yrphostin AG 879 on K v 4.2 and K v 4.3 potassium channels

Background and Purpose A‐type potassium channels ( I A ) are important proteins for modulating neuronal membrane excitability. The expression and activity of K v 4.2 channels are critical for neurological functions and pharmacological inhibitors of K v 4.2 channels may have therapeutic potential for Fragile X syndrome. While screening various compounds, we identified t yrphostin AG 879, a tyrosine kinase inhibitor, as a K v 4.2 inhibitor from. In the present study we characterized the effect of AG 879 on cloned K v 4.2/K v channel‐interacting protein 2 ( KChIP 2) channels. Experimental Approach To screen the library of pharmacologically active compounds, the thallium flux assay was performed on HEK ‐293 cells transiently‐transfected with K v 4.2 c DNA using the M axcyte transfection system. The effects of AG879 were further examined on CHO ‐ K 1 cells expressing K v 4.2/ K ChIP2 channels using a whole‐cell patch‐clamp technique. Key Results Tyrphostin AG 879 selectively and dose‐dependently inhibited K v 4.2 and K v 4.3 channels. In K v 4.2/ KChIP 2 channels, AG 879 induced prominent acceleration of the inactivation rate, use‐dependent block and slowed the recovery from inactivation. AG 879 induced a hyperpolarizing shift in the voltage‐dependence of the steady‐state inactivation of K v 4.2 channels without apparent effect on the V 1/2 of the voltage‐dependent activation. The blocking effect of AG 879 was enhanced as channel inactivation increased. Furthermore, AG 879 significantly inhibited the A ‐type potassium currents in the cultured hippocampus neurons. Conclusion and Implications AG 879 was identified as a selective and potent inhibitor the K v 4.2 channel. AG 879 inhibited K v 4.2 channels by preferentially interacting with the open state and further accelerating their inactivation.