Pico145 (HC-608) is a TRPC1/4/5 channel inhibitor, which can inhibit the TRPC4/TRPC5 channels activated by (-)-englerin A with the IC50 values of 0.349 and 1.3nM, respectively [1]. Pico145 can bind to up to four lipid binding sites between the TRPC5 subunits and replace the phospholipids that interact with the channel pore helices [2]. Pico145 has been widely used to inhibit intracellular Ca2+ influx in cells and to screen agonists of TRPC1/4/5 channels[3].
In vitro, Pico145 treatment (10nM) for 48 hours significantly inhibited (-)-englerin A-induced cell death in SW982 cells and restored cell viability[4]. Treatment with 100nM Pico145 for 15 minutes blocked the sustained firing of CA1 pyramidal cells[5].
In vivo, Pico145 treatment via daily intraperitoneal injection at a dose of 0.1mg/kg for 5 days led to the impairment of spatial memory extinction in Trpc1−/− mice[6].
References:
[1] Rubaiy H N, Ludlow M J, Henrot M, et al. Picomolar, selective, and subtype-specific small-molecule inhibition of TRPC1/4/5 channels[J]. Journal of Biological Chemistry, 2017, 292(20): 8158-8173.
[2] Wright D J, Simmons K J, Johnson R M, et al. Human TRPC5 structures reveal interaction of a xanthine-based TRPC1/4/5 inhibitor with a conserved lipid binding site[J]. Communications Biology, 2020, 3(1): 704.
[3] Rubaiy H N, Ludlow M J, Siems K, et al. Tonantzitlolone is a nanomolar potency activator of transient receptor potential canonical 1/4/5 channels[J]. British Journal of Pharmacology, 2018, 175(16): 3361-3368.
[4] Muraki K, Ohnishi K, Takezawa A, et al. Na+ entry through heteromeric TRPC4/C1 channels mediates (−) Englerin A-induced cytotoxicity in synovial sarcoma cells[J]. Scientific reports, 2017, 7(1): 16988.
[5] Arboit A, Reboreda A, Yoshida M. Involvement of TRPC4 and 5 channels in persistent firing in hippocampal CA1 pyramidal cells[J]. Cells, 2020, 9(2): 365.
[6] Yerna X, Schakman O, Ratbi I, et al. Role of the TRPC1 channel in hippocampal long-term depression and in spatial memory extinction[J]. International journal of molecular sciences, 2020, 21(5): 1712.
Pico145 (HC-608)是一种TRPC1/4/5通道抑制剂，可抑制(-)-englerin A激活的TRPC4/TRPC5通道，IC50值分别为0.349nM和1.3nM[1]。Pico145可与TRPC5亚基之间多达四个脂质结合位点结合，并取代与通道孔螺旋相互作用的磷脂[2]。Pico145已被广泛用于抑制细胞内的Ca2+内流以及筛选TRPC1/4/5通道的激动剂[3]。
在体外，使用10nM的Pico145处理SW982细胞48小时，显著抑制了(-)-englerin A诱导的细胞死亡并恢复了细胞活力[4]。使用100nM的Pico145处理15分钟，阻断了CA1锥体细胞的持续放电[5]。
在体内，每日腹腔注射0.1mg/kg剂量的Pico145，连续5天，导致Trpc1−/−小鼠的空间记忆消退受损[6]。