Calcium-Sensing Receptor and Transient Receptor Ankyrin-1 Mediate Emesis Induction by Deoxynivalenol (Vomitoxin)
Calcium-Sensing Receptor and Transient Receptor Ankyrin-1 Mediate Emesis Induction by Deoxynivalenol (Vomitoxin)
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DOI：
10.1093/toxsci/kfw191
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发表时间：
2017
影响因子：
3.8
通讯作者：
Wenda Wu;Hui-Ren Zhou;S. Bursian;J. Link;J. Pestka
中科院分区：
文献类型：
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作者：
Wenda Wu;Hui-Ren Zhou;S. Bursian;J. Link;J. Pestka
常见的食源性真菌毒素脱氧雪腐镰刀菌烯醇（DON，呕吐毒素）可通过引起拒食和呕吐对动物和人类健康产生负面影响。肠内分泌细胞（EECs）分泌激素介导DON的厌食和呕吐作用。在利用克隆的EEC模型的先前工作中，我们的实验室发现，DON诱导的钙敏感受体（CaSR）（G偶联蛋白受体（GPCR））和瞬时受体锚蛋白-1（TRPA 1）（瞬时受体电位（TRP）通道）的激活驱动Ca 2+介导的激素分泌。与这些体外研究结果一致，CaSR和TRPA 1介导DON诱导的饱腹激素释放和小鼠（一种不能呕吐的动物模型）的拒食。然而，这种GPCR和TRP在DON的催吐作用中的作用仍有待确定。为了解决这个问题，我们测试了DON通过激活CaSR和TRPA 1触发水貂呕吐的假设。口服灌胃选择性激动剂的CaSR（R-568）或TRPA 1（异硫氰酸烯丙酯; AITC）迅速引起水貂呕吐的剂量依赖性方式。口服预处理的动物与CaSR拮抗剂ESTA-2143或TRP拮抗剂钌红（RR），分别抑制这些反应。更重要的是，经口预处理的顺铂-2143或RR对水貂的DON诱导呕吐也有类似的抑制作用。此外，这些拮抗剂抑制并发DON诱导的血浆肽YY 3 -36和5-羟色胺激素的升高，以前证明介导的毒素的水貂呕吐作用。此外，拮抗剂联合治疗可叠加抑制DON诱导的呕吐和肽YY 3-36释放。总之，这里的观察结果强烈表明，CaSR和TRPA 1的激活可能在DON诱导的呕吐中起关键作用。
The common foodborne mycotoxin deoxynivalenol (DON, vomitoxin) can negatively impact animal and human health by causing food refusal and vomiting. Gut enteroendocrine cells (EECs) secrete hormones that mediate DON’s anorectic and emetic effects. In prior work utilizing a cloned EEC model, our laboratory discovered that DON-induced activation of calcium-sensing receptor (CaSR), a G-coupled protein receptor (GPCR), and transient receptor ankyrin-1 (TRPA1), a transient receptor potential (TRP) channel, drives Ca2+-mediated hormone secretion. Consistent with these in vitro findings, CaSR and TRPA1 mediate DON-induced satiety hormone release and food refusal in the mouse, an animal model incapable of vomiting. However, the roles of this GPCR and TRP in DON’s emetic effects remain to be determined. To address this, we tested the hypothesis that DON triggers emesis in mink by activating CaSR and TRPA1. Oral gavage with selective agonists for CaSR (R-568) or TRPA1 (allyl isothiocyanate; AITC) rapidly elicited emesis in the mink in dose-dependent fashion. Oral pretreatment of the animals with the CaSR antagonist NPS-2143 or the TRP antagonist ruthenium red (RR), respectively, inhibited these responses. Importantly, DON-induced emesis in mink was similarly inhibited by oral pretreatment with NPS-2143 or RR. In addition, these antagonists suppressed concurrent DON-induced elevations in plasma peptide YY3-36 and 5-hydroxytryptamine—hormones previously demonstrated to mediate the toxin’s emetic effects in mink. Furthermore, antagonist co-treatment additively suppressed DON-induced emesis and peptide YY 3-36 release. To summarize, the observations here strongly suggest that activation of CaSR and TRPA1 might have critical roles in DON-induced emesis.