靶向氯离子通道：对海洋毒素 Azaspiracid 作用机制的新见解,Chemical Research in Toxicology

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靶向氯离子通道：对海洋毒素 Azaspiracid 作用机制的新见解
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2021-01-29 , DOI: 10.1021/acs.chemrestox.0c00494
Andrea Boente-Juncal ₁ , Sandra Raposo-García ₁ , M Carmen Louzao ₁ , Carmen Vale ₁ , Luis M Botana ₁

Affiliation

Azaspiracids (AZAs) 是由属于Azadinium和Amphidoma属的甲藻产生的海洋毒素在食用受污染的渔业产品（例如贻贝）后导致人类中毒。然而，AZA 诱导细胞毒性和神经毒性作用的确切机制仍然未知。在这项研究中，采用了几种药理学方法来评估阴离子通道对 AZA 作用的作用，证明细胞阴离子失调与这些化合物的毒性作用有关。这里展示的结果表明，体积调节阴离子通道 (VRACs) 受这组毒素的影响，并且因为除了 GTPγ-S 分子的细胞内应用外，没有任何特定的 VRACs 激活剂，这组天然化合物可以代表分析这些通道在细胞稳态中的作用的强大工具。除此之外，在这部作品中，为了阐明人类 HEK293 细胞中存在的阴离子通道以及它们受海洋毒素氮杂螺酸的调节，进行了详细的药理学方法。总而言之，这里提供的数据表明，氮杂螺酸在人体细胞中的作用完全依赖于 ATP 调节的阴离子通道，这些毒素对阴离子通道的上调可能导致调节量减少，并成为报道的这些化合物毒性的基础。

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Targeting Chloride Ion Channels: New Insights into the Mechanism of Action of the Marine Toxin Azaspiracid

Azaspiracids (AZAs) are marine toxins produced by dinoflagellates belonging to the genera Azadinium and Amphidoma that caused human intoxications after consumption of contaminated fishery products, such as mussels. However, the exact mechanism for the AZA induced cytotoxic and neurotoxic effects is still unknown. In this study several pharmacological approaches were employed to evaluate the role of anion channels on the AZA effects that demonstrated that cellular anion dysregulation was involved in the toxic effects of these compounds. The results presented here demonstrated that volume regulated anion channels (VRACs) are affected by this group of toxins, and, because there is not any specific activator of VRACs besides the intracellular application of GTPγ-S molecule, this group of natural compounds could represent a powerful tool to analyze the role of these channels in cellular homeostasis. In addition to this, in this work, a detailed pharmacological approach was performed in order to elucidate the anion channels present in human HEK293 cells as well as their regulation by the marine toxins azaspiracids. Altogether, the data presented here demonstrated that the effect of azaspiracids in human cells was completely dependent on ATP-regulated anion channels, whose upregulation by these toxins could lead to regulatory volume decrease and underlie the reported toxicity of these compounds.

更新日期：2021-03-15

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