Effect of tyrphostin AG879 on K_v4.2 and K_v4.3 potassium channels

Abstract

Background and Purpose A‐type potassium channels (IA) are important proteins for modulating neuronal membrane excitability. The expression and activity of Kv4.2 channels are critical for neurological functions and pharmacological inhibitors of Kv4.2 channels may have therapeutic potential for Fragile X syndrome. While screening various compounds, we identified tyrphostin AG879, a tyrosine kinase inhibitor, as a Kv4.2 inhibitor from. In the present study we characterized the effect of AG879 on cloned Kv4.2/Kv channel‐interacting protein 2 (KChIP2) channels. Experimental Approach To screen the library of pharmacologically active compounds, the thallium flux assay was performed on HEK‐293 cells transiently‐transfected with Kv4.2 cDNA using the Maxcyte transfection system. The effects of AG879 were further examined on CHO‐K1 cells expressing Kv4.2/KChIP2 channels using a whole‐cell patch‐clamp technique. Key Results Tyrphostin AG879 selectively and dose‐dependently inhibited Kv4.2 and Kv4.3 channels. In Kv4.2/KChIP2 channels, AG879 induced prominent acceleration of the inactivation rate, use‐dependent block and slowed the recovery from inactivation. AG879 induced a hyperpolarizing shift in the voltage‐dependence of the steady‐state inactivation of Kv4.2 channels without apparent effect on the V1/2 of the voltage‐dependent activation. The blocking effect of AG879 was enhanced as channel inactivation increased. Furthermore, AG879 significantly inhibited the A‐type potassium currents in the cultured hippocampus neurons. Conclusion and Implications AG879 was identified as a selective and potent inhibitor the Kv4.2 channel. AG879 inhibited Kv4.2 channels by preferentially interacting with the open state and further accelerating their inactivation.

A cell-based high-throughput screen identifies tyrphostin AG 879 as an inhibitor of animal cell phospholipid and fatty acid biosynthesis

“…This makes phospholipid/fatty acid biosynthesis inhibitors attractive treatments of short-term pathologies such as influenza infection since such treatment may be well tolerated. While this evidence is compelling, AG879 has been shown to inhibit other cell processes [ 49 ] so it is not yet possible to say that its antiviral properties are a direct result of its inhibition of host fatty acid or phospholipid biosynthesis.…”

A Small-Molecule Compound Selectively Activates K2P Channel TASK-3 by Acting at Two Distant Clusters of Residues

“…Before the HTS, HEK293 cell lines stably expressing human TASK-3 or its closest homolog TASK-1 were established, because selective active compounds for the TASK subfamily would have a greater tendency to exhibit selectivity among the K2P family. Then, the channel activity was measured by a thallium flux assay as in previous work (Yu et al, 2015;Yue et al, 2016).…”