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首页> 外文期刊>Cellular Signalling >Two G protein-coupled receptors activate Na+/H+ exchanger isoform 1 in Chinese hamster lung fibroblasts through an ERK-dependent pathway
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Two G protein-coupled receptors activate Na+/H+ exchanger isoform 1 in Chinese hamster lung fibroblasts through an ERK-dependent pathway

机译：两个G蛋白偶联受体通过ERK依赖性途径激活中国仓鼠肺成纤维细胞中的Na + / H +交换异构体1

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摘要

The sodium hydrogen exchanger isoform 1 (NHE1) is present in nearly all cells. Regulation of proton flux via the exchanger is a permissive step in cell growth and tumorgenesis and is vital in control of cell volume. The regulation of NHE1 by growth factors involves the Ras-extracellular signal regulated kinase (ERK) pathway, however, the mechanism for G protein-coupled receptor (GPCR) activation of NHE1 is not well established. In this report, the relationship between GPCRs, ERK, and NHE1 in CCL39 cells is investigated. We give evidence that two agonists, the specific alpha(1)-adrenergic agonist, phenylephrine and the water-soluble lipid mitogen, lysophosphatidic acid (LPA) activate NEH1 in CCL39 cells. Activation of ERK by phenylephrine and LPA occurs in a dose- and time-dependent manner. Optimal ERK activation was observed at 10 min and displayed a maximum stimulation at 100 muM phenylephrine and 10 muM LPA. alpha(1)-Adrenergic stimulation also led to a rise in steady-state pH(i) of 0.16 +/- 0.02 pH units, and incubation with LPA induced a 0.43 +/- 0.06 pH unit increase in pH(i). Phenylephrine-induced activation of NHE1 transport and ERK activity was inhibited by pretreating the cells with the MEK inhibitor PD98059. While only half of the LPA activatable exchange activity was abolished by PD98059 and U0126. To further demonstrate the specificity of the phenylephrine and LPA regulation of NHE1 and ERK, CCL39 cells were transfected with a kinase inactive MEK. The data indicate that ERK activation is essential for phenylephrine stimulation of NHE1, and that ERK and RhoA are involved in LPA stimulation of NHE1 by more than one mechanism. In addition, evidence of the convergence of these two pathways is shown by the loss of NHE1 activity when both pathways are inhibited and by the partial additivity of the two agonists on ERK and NHE1 activity. These studies indicate a direct involvement of ERK in the alpha(1)-adrenergic activation of NHE1 and a significant role for both ERK and RhoA in LPA stimulation of NHE1 in CCL39 fibroblasts. (C) 2004 Elsevier Inc. All rights reserved.
机译：几乎所有细胞中都存在钠氢交换异构体1（NHE1）。通过交换器调节质子通量是细胞生长和肿瘤发生中的允许步骤，并且对于控制细胞体积至关重要。生长因子对NHE1的调节涉及Ras-细胞外信号调节激酶（ERK）途径，但是，对NHE1的G蛋白偶联受体（GPCR）激活的机制尚不明确。在此报告中，研究了CCL39细胞中GPCR，ERK和NHE1之间的关系。我们提供的证据表明，两种激动剂，即特定的α（1）-肾上腺素能激动剂，去氧肾上腺素和水溶性脂质有丝分裂原，溶血磷脂酸（LPA）激活CCL39细胞中的NEH1。苯肾上腺素和LPA对ERK的激活呈剂量和时间依赖性。在10分钟时观察到最佳的ERK激活，并在100μM的去氧肾上腺素和10μM的LPA上表现出最大的刺激作用。 α（1）-肾上腺素刺激还导致稳态pH（i）升高0.16 +/- 0.02 pH单位，与LPA一起孵育会导致pH（i）升高0.43 +/- 0.06 pH单位。苯肾上腺素诱导的NHE1转运活化和ERK活性可通过用MEK抑制剂PD98059预处理细胞来抑制。虽然只有一半的LPA可激活的交换活性被PD98059和U0126废除了。为了进一步证明去氧肾上腺素和LPA调节NHE1和ERK的特异性，将CCL39细胞用激酶失活的MEK转染。数据表明，ERK激活对于去氧肾上腺素刺激NHE1是必不可少的，并且ERK和RhoA通过不止一种机制参与了LPA对NHE1的刺激。另外，当两种途径均被抑制时，NHE1活性的丧失以及两种激动剂对ERK和NHE1活性的部分加和表明了这两种途径的融合证据。这些研究表明ERK直接参与NHE1的α（1）-肾上腺素激活，并且ERK和RhoA在LPA刺激CCL39成纤维细胞中发挥重要作用。 （C）2004 Elsevier Inc.保留所有权利。

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