Transient receptor potential vanilloid 4 (TRPV4) regulation of ATP release by the ATP transporter VNUT: a novel therapeutic target for gastrointestinal baro-reception and chronic inflammation
Transient receptor potential vanilloid 4 (TRPV4) regulation of ATP release by the ATP transporter VNUT: a novel therapeutic target for gastrointestinal baro-reception and chronic inflammation
复制标题
瞬时受体电位香草酸 4 (TRPV4) 通过 ATP 转运蛋白 VNUT 调节 ATP 释放：胃肠道压力接收和慢性炎症的新型治疗靶点
DOI：
10.1159/000504021
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发表时间：
2019
期刊：
影响因子：
3.2
通讯作者：
Sugiyama T et al.
中科院分区：
文献类型：
--
作者：
Mihara H;Sugiyama T et al.
研究背景瞬时受体电位香草酸4（TRPV 4）可被拉伸（机械）、温热、某些环氧二十碳三烯酸和脂多糖激活。TRPV4在整个胃肠道上皮细胞中表达，其活化诱导参与内脏高敏感性的三磷酸腺苷（ATP）胞吐。囊泡核苷酸转运蛋白（VNUT）是一种ATP转运蛋白，可介导ATP在分泌囊泡中的储存和ATP在刺激后的胞吐释放。胃肠道上皮细胞也通过分子机制释放ATP以响应低渗透压或酸，但尚不清楚。这些协同释放的ATP可能参与内脏高敏感性。低浓度的第一代双磷酸盐氯膦酸盐（clodronate）可抑制VNUT活性，因此氯膦酸盐可能是一种安全有效的内脏痛治疗药物。（3）抑制VNUT可能成为治疗功能性胃肠疾病的新策略。
BackgroundTransient receptor potential vanilloid 4 (TRPV4) is activated by stretch (mechanical), warm temperature, some epoxyeicosatrienoic acids, and lipopolysaccharide. TRPV4 is expressed throughout the gastrointestinal epithelia and its activation induces adenosine triphosphate (ATP) exocytosis that is involved in visceral hypersensitivity. As an ATP transporter, vesicular nucleotide transporter (VNUT) mediates ATP storage in secretory vesicles and ATP release via exocytosis upon stimulation.SummaryTRPV4 is sensitized under inflammatory conditions by a variety of factors, including proteases and serotonin, whereas methylation-dependent silencing of TRPV4 expression is associated with various pathophysiological conditions. Gastrointestinal epithelia also release ATP in response to hypo-osmolality or acid through molecular mechanisms that remain unclear. These synergistically released ATP could be involved in visceral hypersensitivity. Low concentrations of the first generation bisphosphate, clodronate, were recently reported to inhibit VNUT activity and thus clodronate may be a safe and potent therapeutic option to treat visceral pain.Key MessagesThis review focuses on:(1) ATP and TRPV4 activities in gastrointestinal epithelia;(2) factors that could modulate TRPV4 activity in gastrointestinal epithelia; and (3) the inhibition of VNUT as a potential novel therapeutic strategy for functional gastrointestinal disorders.