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首页> 外文期刊>American Journal of Physiology >EGF receptor transactivation and MAP kinase mediate proteinase-activated receptor-2-induced chloride secretion in intestinal epithelial cells
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EGF receptor transactivation and MAP kinase mediate proteinase-activated receptor-2-induced chloride secretion in intestinal epithelial cells

机译：EGF受体反式激活和MAP激酶介导蛋白酶激活的受体2诱导的肠上皮细胞的氯离子分泌

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First published November 21, 2007; doi:10.H52/ajpgi.00303.2007.-We examined the stimulus-secretion pathways whereby proteinase-activated receptor 2 (PAR-2) stimulates Cl~ secretion in intestinal epithelial cells. SCBN and T84 epithelial monolayers grown on Snapwefl supports and mounted in modified Ussing chambers were activated by the PAR-2-activating peptides SLIGRL-NH2 and 2-furoyl-LIGRLO-NH2. Short-circuit current (I_(sc)) was used as a measure of net electrogenic ion transport. Basolateral, but not apical, application of SLIGRL-NH2 or 2-furoyl-LIGRLO-NH2 caused a concentration-dependent change in I_(sc) that was significantly reduced in Cl~- free buffer and by the intracellular Ca~(2+) blockers thapsigargin and BAPTA-AM, but not by the Ca~(2+) channel blocker verapamil. Inhibitors of PKA (H-89) and CFTR (glibenclamide) also significantly reduced PAR-2-stimulated Cl~ transport. PAR-2 activation was associated with increases in cAMP and intracellular Ca~(2+). Immunoblot analysis revealed increases inphosphorylation of epidermal growth factor (EGF) receptor (EGFR) tyrosine kinase, Src, Pyk2, cRaf, and ERK1/2 in response to PAR-2 activation. Pretreatment with inhibitors of cyclooxygenases (indomethacin), tyrosine kinases (genistein), EGFR (PD~(-1)53035), MEK (PD-98059 or U-0126), and Src (PP1) inhibited SLIGRL-NHb-induced increases in I_(sc). Inhibition of Src, but not matrix metalloproteinases, reduced EGFR phosphorylation. Reduced EGFR phosphorylation paralleled the reduction in PAR-2-stimulated I_(sc). We conclude that activation of basolateral, but not apical, PAR-2 induces epithelial Cl~ secretion via cAMP- and Ca~(2+)-dependent mechanisms. The secretory effect involves EGFR transactivation by Src, leading to subsequent ERK1/2 activation and increased cyclooxygenase activity.
机译：首次发布于2007年11月21日; doi：10.H52 / ajpgi.00303.2007.-我们研究了刺激分泌途径，其中蛋白酶激活的受体2（PAR-2）刺激肠道上皮细胞内的C1分泌。在Snapwefl支架上生长并安装在改良的Ussing室中的SCBN和T84上皮单层被PAR-2-激活肽SLIGRL-NH2和2-呋喃基-LIGRLO-NH2激活。短路电流（I_（sc））被用作净电离子迁移的量度。 SLIGRL-NH2或2-呋喃基-LIGRLO-NH2的基底外侧但非根尖的应用引起了I_（sc）的浓度依赖性变化，该变化在无Cl〜-缓冲液和细胞内Ca〜（2+）明显降低阻滞剂thapsigargin和BAPTA-AM，但不被Ca〜（2+）通道阻滞剂维拉帕米所抑制。 PKA（H-89）和CFTR（格列本脲）的抑制剂也显着减少PAR-2刺激的Cl〜转运。 PAR-2的激活与cAMP和细胞内Ca〜（2+）的增加有关。免疫印迹分析显示，响应PAR-2激活，表皮生长因子（EGF）受体（EGFR）酪氨酸激酶，Src，Pyk2，cRaf和ERK1 / 2的磷酸化增加。用环氧合酶（吲哚美辛），酪氨酸激酶（染料木黄酮），EGFR（PD〜（-1）53035），MEK（PD-98059或U-0126）和Src（PP1）抑制剂进行预处理可抑制SLIGRL-NHb引起的SCI增加I_（sc）。抑制Src而不是基质金属蛋白酶可降低EGFR磷酸化。 EGFR磷酸化的减少与PAR-2刺激的I_（sc）的减少平行。我们得出结论，激活基底外侧而不是根尖的PAR-2可以通过cAMP-和Ca〜（2+）依赖性机制诱导上皮Cl〜分泌。分泌作用涉及Src激活EGFR，从而导致随后的ERK1 / 2激活和环氧合酶活性增加。

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