Scalaradial Is a Potent Inhibitor of Transient Receptor Potential Melastatin 2 (TRPM2) Ion Channels.
Scalaradial Is a Potent Inhibitor of Transient Receptor Potential Melastatin 2 (TRPM2) Ion Channels.
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DOI：
10.1021/acs.jnatprod.7b00515
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发表时间：
2017-10-27
影响因子：
5.1
通讯作者：
Horgen FD
中科院分区：
文献类型：
--
作者：
Starkus JG;Poerzgen P;Layugan K;Kawabata KG;Goto JI;Suzuki S;Myers G;Kelly M;Penner R;Fleig A;Horgen FD
TRPM 2是一种Ca 2+可渗透的非选择性阳离子通道，在氧化剂诱导的细胞死亡、胰岛素分泌和细胞因子释放中发挥作用。很少有TRPM 2抑制剂被报道，这阻碍了TRPM 2作为药物靶点的验证。在筛选我们的内部海洋衍生化学文库时，我们将scalaradial和12-脱乙酰基scalaradial鉴定为Cacospongia（Demospongiae类，Thorectidae家族）的未描述物种的提取物中的活性组分，其强烈抑制TRPM 2过表达HEK 293细胞中TRPM 2介导的Ca 2+内流。在全细胞膜片钳实验中，Scalaradial（以及类似的12-去乙酰基Scalaradial）以浓度和时间依赖性方式抑制TRPM 2介导的电流（约20分钟至完全发作; IC 50 210 nM）。Scalaradial抑制TRPM 7的效力较低（IC 50 760 nM），但在全细胞膜片钳实验中未能抑制CRAC、TRPM 4和TRPV 1电流。Scalaradial对TRPM 2通道的作用与其众所周知的抑制分泌型磷脂酶A2（sPLA 2）的能力及其对细胞外信号调节激酶（ERK）和Akt途径的作用无关。此外，在大鼠胰岛素瘤细胞系中，Scalaradial显示出抑制内源性TRPM 2电流（IC 50 330 nM）。基于其效力和新兴的特异性特征，scalaradial是少数已知TRPM 2抑制剂的重要补充。
TRPM2 is a Ca2+-permeable, nonselective cation channel that plays a role in oxidant-induced cell death, insulin secretion, and cytokine release. Few TRPM2 inhibitors have been reported, which hampers the validation of TRPM2 as a drug target. While screening our in-house marine-derived chemical library, we identified scalaradial and 12-deacetylscalaradial as the active components within an extract of an undescribed species of Cacospongia (class Demospongiae, family Thorectidae) that strongly inhibited TRPM2-mediated Ca2+ influx in TRPM2-overexpressing HEK293 cells. In whole-cell patch-clamp experiments, scalaradial (and similarly 12-deacetylscalaradial) inhibited TRPM2-mediated currents in a concentration- and time-dependent manner (~20 min to full onset; IC50 210 nM). Scalaradial inhibited TRPM7 with less potency (IC50 760 nM) but failed to inhibit CRAC, TRPM4, and TRPV1 currents in whole-cell patch clamp experiments. Scalaradial’s effect on TRPM2 channels was shown to be independent of its well-known ability to inhibit secreted phospholipase A2 (sPLA2) and its reported effects on extracellular signal-regulated kinases (ERK) and Akt pathways. In addition, scalaradial was shown to inhibit endogenous TRPM2 currents in a rat insulinoma cell line (IC50 330 nM). Based on its potency and emerging specificity profile, scalaradial is an important addition to the small number of known TRPM2 inhibitors.
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影响因子：
5.8
作者：
BOYER, CS;BANNENBERG, GL;MOLDEUS, P
通讯作者：
MOLDEUS, P
影响因子：
7.3
作者：
Arumugam, TV;Arnold, N;Taylor, SM
通讯作者：
Taylor, SM
影响因子：
7.3
作者：
Fonfria, E;Marshall, ICB;McNulty, S
通讯作者：
McNulty, S
影响因子：
16
作者：
Hara, Y;Wakamori, M;Mori, Y
通讯作者：
Mori, Y
DOI：
10.1007/978-3-642-54215-2_16
发表时间：
2014-01-01
期刊：
MAMMALIAN TRANSIENT RECEPTOR POTENTIAL (TRP) CATION CHANNELS, VOL I
影响因子：
--
作者：
Faouzi, Malika;Penner, Reinhold
通讯作者：
Penner, Reinhold