Abstract

K2P potassium channels stabilize the resting membrane potential in nearly all cells and have been implicated in several neuronal, cardiovascular, and immune diseases. DCPIB, a known specific and potent inhibitor of volume-regulated anion channels (VRAC), has been reported to activate TREK1 and TREK2 in astrocytes and in vitro recently. In the present study, we demonstrated DCPIB also voltage dependently activated TRAAK besides TREK1/TREK2, showing DCPIB activated all TREK subfamily members. In contrast, the compound potently inhibited several other K2P channels with no voltage dependence, including TRESK, TASK1, and TASK3. DCPIB displayed superior selectivity toward TRESK with an IC₅₀ of 0.14 μM, demonstrating at least 100-fold higher affinity over TREK1/TRAAK channels. Furthermore, the impaired ion selectivity filter region greatly impaired the activating effect of DCPIB on TREK1 but not the inhibitory effect of DCPIB on TRESK. This indicates distinct molecular determinants underlying the effect of DCPIB on TREK1 or TRESK channels. Our results showed that DCPIB played diverse effects on K2P channels and could be a useful tool for further investigating structure–function studies of K2P channels.