Molecular Mechanism of Stimulation of Na-K-ATPase by Leukotriene D4 in Intestinal Epithelial Cells.
Molecular Mechanism of Stimulation of Na-K-ATPase by Leukotriene D4 in Intestinal Epithelial Cells.
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DOI：
10.3390/ijms22147569
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发表时间：
2021-07-15
影响因子：
5.6
通讯作者：
Sundaram U
中科院分区：
文献类型：
--
作者：
Nepal N;Arthur S;Butts MR;Singh S;Palaniappan B;Sundaram U
Na-K-ATPase为肠上皮细胞钠依赖的营养转运体的功能提供了良好的跨细胞钠梯度。肠细胞的主要代谢产物是谷氨酰胺，它通过肠隐窝细胞中的Na-谷氨酰胺共转运体(SN2；SLC38A5)被吸收。SN2活性在慢性肠炎时被刺激，至少部分是由于Na-K-ATPase活性的刺激。已知白三烯D4(LTD4)在慢性肠炎时粘膜中升高，但其调节Na-K-ATPase的方式尚不清楚。在大鼠肠上皮细胞(IEC-18)的体外模型中，LTD4对Na-K-ATPase活性有明显的刺激作用。由于LTD4通过钙依赖的蛋白激酶C(PKC)介导其作用，因此测定了钙水平并发现其升高。PKC激活剂佛波酯(PMA)也像LTD4一样介导Na-K-ATPase的激活，而BAPTA-AM(钙络合剂)和Calphostin-C(CaL-C；PKC抑制剂)则抑制Na-K-ATPase的激活。LTD_4引起Na-K-ATP酶α_1和β_1亚单位的表达显著增加，而钙磷蛋白-C可抑制这种作用。这些结果表明，LTD_4通过钙激活的α途径，继而激活肠隐窝细胞的Na-K-ATPase，进而增加Na-K-ATPaseβ1和PK1亚单位的转录。
Na-K-ATPase provides a favorable transcellular Na gradient required for the functioning of Na-dependent nutrient transporters in intestinal epithelial cells. The primary metabolite for enterocytes is glutamine, which is absorbed via Na-glutamine co-transporter (SN2; SLC38A5) in intestinal crypt cells. SN2 activity is stimulated during chronic intestinal inflammation, at least in part, secondarily to the stimulation of Na-K-ATPase activity. Leukotriene D4 (LTD4) is known to be elevated in the mucosa during chronic enteritis, but the way in which it may regulate Na-K-ATPase is not known. In an in vitro model of rat intestinal epithelial cells (IEC-18), Na-K-ATPase activity was significantly stimulated by LTD4. As LTD4 mediates its action via Ca-dependent protein kinase C (PKC), Ca levels were measured and were found to be increased. Phorbol 12-myristate 13-acetate (PMA), an activator of PKC, also mediated stimulation of Na-K-ATPase like LTD4, while BAPTA-AM (Ca chelator) and calphostin-C (Cal-C; PKC inhibitor) prevented the stimulation of Na-K-ATPase activity. LTD4 caused a significant increase in mRNA and plasma membrane protein expression of Na-K-ATPase α1 and β1 subunits, which was prevented by calphostin-C. These data demonstrate that LTD4 stimulates Na-K-ATPase in intestinal crypt cells secondarily to the transcriptional increase of Na-K-ATPase α1 and β1 subunits, mediated via the Ca-activated PKC pathway.
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