Lysophosphatidic acid inhibits cholera toxin-induced secretory diarrhea through CFTR-dependent protein interactions.
Lysophosphatidic acid inhibits cholera toxin-induced secretory diarrhea through CFTR-dependent protein interactions.
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DOI：
10.1084/jem.20050421
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发表时间：
2005-10-03
期刊：
影响因子：
--
通讯作者：
Naren AP
中科院分区：
文献类型：
--
作者：
Li C;Dandridge KS;Di A;Marrs KL;Harris EL;Roy K;Jackson JS;Makarova NV;Fujiwara Y;Farrar PL;Nelson DJ;Tigyi GJ;Naren AP
囊性纤维化跨膜传导调节因子（CFTR）是一种cAMP调节的氯离子通道，主要位于气道、肠道和外分泌腺上皮细胞的顶端或管腔表面;已充分证实CFTR在霍乱毒素（CTX）诱导的分泌性腹泻中起关键作用。溶血磷脂酸（LPA）是一种存在于血液和食物中的天然磷脂，据报道在胃肠道伤口修复、细胞凋亡、炎症性肠病和腹泻等多种疾病中起着至关重要的作用。在这里，我们首次表明，2型LPA受体（LPA 2）在肠上皮细胞的顶端表面表达，在那里它们通过PSD 95/Dlg/ZO-1相互作用与Na+/H+交换调节因子-2和CFTR形成大分子复合物。LPA通过LPA 2介导的Gi通路抑制CFTR依赖性碘流出，并且LPA以区室化方式抑制CFTR介导的短路电流。CFTR依赖性肠液分泌诱导的CTX在小鼠中大幅减少LPA管理，破坏这种复合物使用细胞渗透LPA 2特异性肽逆转LPA 2介导的抑制。因此，富含LPA的食物可能是治疗某些形式腹泻的替代方法。
The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated chloride channel localized primarily at the apical or luminal surfaces of epithelial cells that line the airway, gut, and exocrine glands; it is well established that CFTR plays a pivotal role in cholera toxin (CTX)-induced secretory diarrhea. Lysophosphatidic acid (LPA), a naturally occurring phospholipid present in blood and foods, has been reported to play a vital role in a variety of conditions involving gastrointestinal wound repair, apoptosis, inflammatory bowel disease, and diarrhea. Here we show, for the first time, that type 2 LPA receptors (LPA2) are expressed at the apical surface of intestinal epithelial cells, where they form a macromolecular complex with Na+/H+ exchanger regulatory factor–2 and CFTR through a PSD95/Dlg/ZO-1–based interaction. LPA inhibited CFTR-dependent iodide efflux through LPA2-mediated Gi pathway, and LPA inhibited CFTR-mediated short-circuit currents in a compartmentalized fashion. CFTR-dependent intestinal fluid secretion induced by CTX in mice was reduced substantially by LPA administration; disruption of this complex using a cell-permeant LPA2-specific peptide reversed LPA2-mediated inhibition. Thus, LPA-rich foods may represent an alternative method of treating certain forms of diarrhea.
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