title: Differential modulation of TWIK-related K+channel (TREK) and TWIK-related acid-sensitive K+channel 2 (TASK2) activity by pyrazole compounds.
abstract: 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 (ITREK1), TREK-2 (ITREK2), and TASK2 current (ITASK-2) with half-maximal inhibitory concentrations (IC50) of 0.89±0.27, 1.95±1.44, and 2.42±0.39µM, respectively. BTP2 slightly inhibited ITASK-2(80.3±2.5% at 100μM). In contrast, pyr6 at 100µM potentiated ITREK1 andITREK2by approximately 2.6- and 3.6-fold compared to the control and inhibited ITASK2(38.7±9.2%). Pyr10 showed a subtype-specific inhibition of ITREK1but not ITREK2. It also inhibited ITASK2(70.9±3.1% at 100μM). 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.
authors: Department of Physiology, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea; Channelopathy Research Center (CRC), Dongguk University College of Medicine, Goyang 10326, Republic of Korea.
authors: Hyun Jong
authors: HJ
authors: Kim
authors: Department of Physiology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors: Joohan
authors: J
authors: Woo
authors: Department of Physiology, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea; Channelopathy Research Center (CRC), Dongguk University College of Medicine, Goyang 10326, Republic of Korea.
authors: Yuran
authors: Y
authors: Nam
authors: Department of Physiology, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea; Channelopathy Research Center (CRC), Dongguk University College of Medicine, Goyang 10326, Republic of Korea. Electronic address: jh_nam@dongguk.ac.kr.
authors: Joo Hyun
authors: JH
authors: Nam
authors: Department of Physiology, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea; Department of Internal Medicine Graduate School of Medicine, Dongguk University, Goyang 10326, Republic of Korea. Electronic address: wk2kim@naver.com.
authors: Woo Kyung
authors: WK
authors: Kim
mesh_terms: D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology*; D024683:Potassium Channels, Tandem Pore Domain / Q000378:metabolism*; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C410295:KCNK5 protein, human; D026902:Potassium Channel Blockers; D024683:Potassium Channels, Tandem Pore Domain; D011720:Pyrazoles; C103742:potassium channel protein TREK-1; D002118:Calcium
keywords: Calcium signaling; Potassium channels; Pyrazole derivative; TASK-2; TREK-1; TREK-2