Involvement of VNUT-exocytosis in transient receptor potential vanilloid 4-dependent ATP release from gastrointestinal epithelium.
Involvement of VNUT-exocytosis in transient receptor potential vanilloid 4-dependent ATP release from gastrointestinal epithelium.
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DOI：
10.1371/journal.pone.0206276
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Moriyama Y
中科院分区：
文献类型：
--
作者：
Mihara H;Uchida K;Koizumi S;Moriyama Y
三磷酸腺苷（ATP）调节胃肠道中的机械敏感迷走传入神经。ATP通过ATP转运蛋白VNUT储存在分泌囊泡中。最近，据报道，二磷酸氯膦酸盐抑制VNUT，并被认为是一种安全有效的治疗慢性疼痛的选择。瞬时受体电位香草酸4（TRPV 4）被机械刺激和一些环氧二十碳三烯酸激活，并在炎症条件下变得敏感。我们以前报道过TRPV 4和VNUT在小鼠食管角化细胞中表达，TRPV 4激活诱导胃上皮细胞ATP释放。在这里，我们显示了TRPV 4和VNUT在正常人胃肠道细胞衍生的细胞系（GES-1和CCD 841）和正常和VNUT-KO小鼠的组织中的表达。TRPV 4激动剂（GSK 101或8，9-EET）在小鼠原代结肠上皮细胞和CCD 841细胞中诱导胞质Ca 2+和/或电流响应的增加，但在从TRPV 4-KO小鼠分离的细胞中不诱导。TRPV 4激动剂（GSK 101或5.6-EET）也诱导GES-1和CCD 841细胞中的ATP释放，这可以被VNUT抑制剂氯膦酸盐阻断。因此，用氯膦酸盐抑制VNUT可能代表内脏疼痛的新的治疗选择。
Adenosine triphosphate (ATP) modulates mechanosensitive vagal afferent nerves in the gastrointestinal tract. ATP is stored in secretory vesicles via the ATP transporter VNUT. Recently, the bisphosphate clodronate was reported to inhibit VNUT and was suggested to be a safe potent therapeutic option for chronic pain. Transient receptor potential vanilloid 4 (TRPV4) is activated by mechanical stimuli and some epoxyeicosatrienoic acids and becomes sensitized under inflammatory conditions. We have previously reported that TRPV4 and VNUT are expressed in mouse esophageal keratinocytes and that TRPV4 activation induces ATP release in gastric epithelial cells. Here we show the expression of TRPV4 and VNUT in normal human gastrointestinal cell derived cell lines (GES-1 and CCD 841) and in tissues from normal and VNUT-KO mice. TRPV4 agonists (GSK101 or 8,9-EET) induced an increase in cytosolic Ca2+ and/or current responses in mouse primary colonic epithelial cells and CCD 841 cells, but not in cells isolated from TRPV4-KO mice. TRPV4 agonists (GSK101 or 5.6-EET) also induced ATP release in GES-1 and CCD 841 cells, which could be blocked by the VNUT inhibitor, clodronate. Thus, VNUT inhibition with clodronate could represent a novel therapeutic option for visceral pain.
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影响因子：
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作者：
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