Differential modulation of TWIK-related K⁺channel (TREK) and TWIK-related acid-sensitive K⁺channel 2 (TASK2) activity by pyrazole compounds

Pyrazole derivatives were originally suggested as selective blockers of the transient receptor potential cation 3 (TRPC3) and channel. In particular, pyr3 and 10 selectively inhibit TRPC3, whereas pyr2 (BTP2) and 6 inhibit ORAI1. However, their effects on background K⁺channel activity have not been elucidated. In this study, the effects of BTP2, pyr3, pyr6, and pyr10 were studied on cloned human TWIK-related K⁺channels (TREKs) and TWIK-related acid-sensitive K⁺channel 2 (TASK-2) channels, which modulate Ca²⁺signaling by controlling membrane potential, in HEK293T-overexpressing cells by using a whole-cell patch clamp technique. Pyr3 potently inhibited TREK-1 (I_TREK1), TREK-2 (I_TREK2), and TASK2 current (I_TASK-2) with half-maximal inhibitory concentrations (IC₅₀) of 0.89±0.27, 1.95±1.44, and 2.42±0.39 µM, respectively. BTP2 slightly inhibited I_TASK-2(80.3±2.5% at 100 μM). In contrast, pyr6 at 100 µM potentiated I_{TREK1 and}I_TREK2by approximately 2.6- and 3.6-fold compared to the control and inhibited I_TASK2(38.7±9.2%). Pyr10 showed a subtype-specific inhibition of I_TREK1but not I_TREK2. It also inhibited I_TASK2(70.9±3.1% at 100 μM). To the best of our knowledge, this study is the first to describe the differential modulation of TREKs and TASK2 channels by pyrazole derivatives, previously used as inhibitors of TRPC3 and ORAI1. Therefore, studies using these drugs should consider their modulation of other channels such as TREK and TASK-2.