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Scalaradial Is a Potent Inhibitor of Transient Receptor Potential Melastatin 2 (TRPM2) Ion Channels
Journal of Natural Products ( IF 3.3 ) Pub Date : 2017-10-11 00:00:00 , DOI: 10.1021/acs.jnatprod.7b00515 John G. Starkus 1 , Peter Poerzgen 2 , Kristine Layugan 2 , Kelly Galbraith Kawabata 2 , Jun-Ichi Goto 1, 3 , Sayuri Suzuki 1 , George Myers 1 , Michelle Kelly 4 , Reinhold Penner 1, 5 , Andrea Fleig 1, 5 , F. David Horgen 2
Journal of Natural Products ( IF 3.3 ) Pub Date : 2017-10-11 00:00:00 , DOI: 10.1021/acs.jnatprod.7b00515 John G. Starkus 1 , Peter Poerzgen 2 , Kristine Layugan 2 , Kelly Galbraith Kawabata 2 , Jun-Ichi Goto 1, 3 , Sayuri Suzuki 1 , George Myers 1 , Michelle Kelly 4 , Reinhold Penner 1, 5 , Andrea Fleig 1, 5 , F. David Horgen 2
Affiliation
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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.
中文翻译：
Scalaradial是瞬态受体潜在Melastatin 2（TRPM2）离子通道的有效抑制剂。
TRPM2是可渗透Ca 2+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起作用。很少有TRPM2抑制剂的报道，这阻碍了TRPM2作为药物靶标的验证。在筛选我们内部的海洋来源化学库时，我们确定了radi放射菌和12-去乙酰基as放射菌是未描述种类的Cacospongia（类蝇科，Thorectidae科）的提取物中的活性成分，该物种强烈抑制TRPM2介导的Ca 2+内流。 TRPM2过表达的HEK293细胞。在全细胞膜片钳实验中，sc骨（和类似的12-去乙酰基scal骨）以浓度和时间依赖的方式抑制TRPM2介导的电流（约20分钟至完全发作； IC50 210纳米）。在全细胞膜片钳实验中，骨以较低的效价（IC 50 760 nM）抑制TRPM7，但未能抑制CRAC，TRPM4和TRPV1电流。已显示Scalaradial对TRPM2通道的影响与其已知的抑制分泌的磷脂酶A 2（sPLA 2）的能力以及其对细胞外信号调节激酶（ERK）和Akt途径的影响无关。此外，显示sc骨可抑制大鼠胰岛素瘤细胞系（IC 50 330 nM）中的内源性TRPM2电流。基于其功效和新兴的特异性特征，,骨是少量已知TRPM2抑制剂的重要补充。
更新日期：2017-10-11
中文翻译：
Scalaradial是瞬态受体潜在Melastatin 2（TRPM2）离子通道的有效抑制剂。
TRPM2是可渗透Ca 2+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起作用。很少有TRPM2抑制剂的报道，这阻碍了TRPM2作为药物靶标的验证。在筛选我们内部的海洋来源化学库时，我们确定了radi放射菌和12-去乙酰基as放射菌是未描述种类的Cacospongia（类蝇科，Thorectidae科）的提取物中的活性成分，该物种强烈抑制TRPM2介导的Ca 2+内流。 TRPM2过表达的HEK293细胞。在全细胞膜片钳实验中，sc骨（和类似的12-去乙酰基scal骨）以浓度和时间依赖的方式抑制TRPM2介导的电流（约20分钟至完全发作； IC50 210纳米）。在全细胞膜片钳实验中，骨以较低的效价（IC 50 760 nM）抑制TRPM7，但未能抑制CRAC，TRPM4和TRPV1电流。已显示Scalaradial对TRPM2通道的影响与其已知的抑制分泌的磷脂酶A 2（sPLA 2）的能力以及其对细胞外信号调节激酶（ERK）和Akt途径的影响无关。此外，显示sc骨可抑制大鼠胰岛素瘤细胞系（IC 50 330 nM）中的内源性TRPM2电流。基于其功效和新兴的特异性特征，,骨是少量已知TRPM2抑制剂的重要补充。
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