Paxilline is a tremor-causing fungal alkaloid that can effectively inhibit high-conductance Ca2+-activated K+ (BK) channels, with IC50 of approximately 10nM and Ki=1.9nM[1]. Paxilline affects the dynamic balance of intracellular calcium ions and the transmission of electrical signals by blocking BK channels, and is used to explore the reaction and mechanism of BK channels in cellular processes[2]. Paxilline also inhibits muscle/endoplasmic reticulum Ca2+ ATPase, IC50 = 5-50µM[3].
In vitro, Paxilline (4µM) treated HT 22 cells for 18 h had significant cytoprotective effects against glutamate-induced toxicity, independent of BKCa channel activity and oxidative stress induced by glutamate treatment[4]. Paxilline (30µM) treatment of U251 MG, U87 MG, U343 and U251 N glioma cell lines can enhance the TRAIL sensitivity of cells and induce cell apoptosis [5].
In vivo, Paxilline (2.2 and 4.4 µg/kg) administered intraperitoneally to C57BL/6 mice could eliminate tonic-clonic seizures in mice and also reduce the duration and intensity of epileptic seizures[6]. Paxilline (3µg/kg) significantly alleviated thalidomide-induced synaptic and cognitive dysfunction in mice via intraperitoneal injection[7].
References:
[1] Zhou Y, et al. Paxilline inhibits BK channels by an almost exclusively closed-channel block mechanism[J]. Gen Physiol. 2014 Nov;144(5):415-40.
[2] Jackson-Weaver, O., Paredes, D.A., Gonzalez Bosc, L.V., et al. Intermittent hypoxia in rats increases myogenic tone through loss of hydrogen sulfide activation of large-conductance Ca2+-activated potassium channels.[J].Circulation Research 108(12), 2011:1439-1447 .
[3] Knaus H G, McManus O B, Lee S H, et al. Tremorgenic indole alkaloids potently inhibit smooth muscle high-conductance calcium-activated potassium channels. [J]Biochemistry, 1994, 33(19): 5819-5828.
[4] Szewczyk K A .Glutamate-induced cell death in HT22 mouse hippocampal cells is attenuated by paxilline, a BK channel inhibitor[J].Mitochondrion, 2012.
[5]Kang Y J , Kim I Y , Kim E H ,et al.Paxilline enhances TRAIL-mediated apoptosis of glioma cells via modulation of c-FLIP, survivin and DR5[J].Experimental & Molecular Medicine, 2011, 43(1):24.
[6]Sheehan JJ, et al. Anticonvulsant effects of the BK-channel antagonist paxilline. Epilepsia [J].2009. 50(4):711-20.
[7]Tae-Yong Choi, Seung-Hyun Lee, Soo-Jeong Kim, et al. BK channel blocker paxilline attenuates thalidomide-caused synaptic and cognitive dysfunctions in mice[J].Scientific Reports volume 8, 2018: 17653.
Paxilline是一种致震颤真菌生物碱,可有效抑制高电导Ca2+ 激活K+ (BK)通道,IC50约为10nM,Ki=1.9nM[1]。Paxilline通过阻断BK通道,影响细胞内钙离子的动态平衡及电信号的传递,被用于探究BK通道在细胞过程中的反应和作用机理[2]。Paxilline还抑制肌/内质网Ca2+ ATP酶,IC50 = 5-50µM[3]。
在体外,Paxilline(4µM)处理HT 22细胞18h,具有显著的细胞保护作用,免受谷氨酸诱导的毒性,与谷氨酸处理诱导的BKCa通道活性和氧化应激无关[4]。paxilline(30µM)处理U251 MG、U87 MG、U343和U251 N胶质瘤细胞系,可以增强细胞的TRAIL敏感性,诱导细胞凋亡[5]。
在体内,Paxilline(2.2 and 4.4µg/kg)通过腹腔注射给予C57BL/6小鼠,可以消除小鼠的强直阵挛性发作,还可以减少癫痫发作的持续时间和强度[6]。Paxilline(3µg/kg)通过腹腔注射,显著减轻了沙利度胺引起的小鼠突触和认知功能障碍[7]。