Activation of TREK‐1 and TREK‐2 Two‐Pore Domain Potassium Channels by the Kv4 Channel Modulator, NS5806

ABSTRACT NS5806 is a diaryl‐urea small molecule developed for the treatment of pain and neurological disorders. A potent activator of Kv4.3 potassium channels, it is widely used to study Kv4 channel physiology in excitable cells, including trigeminal neurons. Surprisingly, we found that NS5806 produced a significant, robust hyperpolarization of the resting membrane potential of all trigeminal neurons tested. Given the structural similarity of NS5806 to other negatively charged activator compounds with broad potassium channel activity, we investigated whether NS5806 might also modulate the two‐pore domain potassium (K2P) TREK channels, which are abundantly expressed in sensory neurons. Here we show that NS5806 activates both TREK‐1 and TREK‐2 channels. While NS5806 is described as a Kv4‐selective activator, our data suggest that its effects on trigeminal and other neurons may arise from concurrent activation of multiple potassium channel types, including TREK‐1 and TREK‐2.