Prostaglandin I2 Production and cAMP Accumulation in Response to Acidic Extracellular pH through OGR1 in Human Aortic Smooth Muscle Cells*
Prostaglandin I2 Production and cAMP Accumulation in Response to Acidic Extracellular pH through OGR1 in Human Aortic Smooth Muscle Cells*
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DOI：
10.1074/jbc.m505287200
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发表时间：
2005-10
影响因子：
4.8
通讯作者：
H. Tomura;Ju-Qiang Wang;Mayumi Komachi;A. Damirin;C. Mogi;M. Tobo;J. Kon;N. Misawa;Koichi Sato;F. Okajima
中科院分区：
文献类型：
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作者：
H. Tomura;Ju-Qiang Wang;Mayumi Komachi;A. Damirin;C. Mogi;M. Tobo;J. Kon;N. Misawa;Koichi Sato;F. Okajima
卵巢癌 G 蛋白偶联受体 1 (OGR1) 和 GPR4 最近被鉴定为质子敏感或细胞外 pH 响应性 G 蛋白偶联受体，分别刺激磷酸肌醇产生和 cAMP 积累。在本研究中，我们发现 OGR1 和 GPR4 mRNA 在人主动脉平滑肌细胞（AoSMC）中表达。酸性细胞外 pH 诱导磷酸肌醇的产生、细胞内 Ca2+ 浓度 ([Ca2+]i) 的短暂增加以及这些细胞中 cAMP 的积累。当针对 OGR1 和 GPR4 的小干扰 RNA (siRNA) 转染至细胞时，酸诱导的磷酸肌醇产生和 [Ca2+]i 增加被 OGR1 siRNA 显着抑制，但不受 GPR4 siRNA 抑制。出乎意料的是，酸诱导的cAMP积累也很大程度上被OGR1 siRNA抑制，但仅被GPR4 siRNA轻微抑制。酸性细胞外 pH 值还刺激前列腺素 I2 (PGI2) 的产生，但又被 OGR1 siRNA 抑制。细胞外信号调节激酶激酶和环氧合酶的特异性抑制剂减弱了酸诱导的 PGI2 产生和 cAMP 积累，而不改变磷酸肌醇的产生。磷脂酶 C 的特异性抑制剂也抑制酸诱导的 cAMP 积累。总之，OGR1 是参与 AoSMC 中细胞外酸诱导的 PGI2 产生和 cAMP 积累刺激的主要受体。 cAMP 积累可能是通过 OGR1 介导的磷脂酶 C/环氧合酶/PGI2 途径的刺激而发生的。
Ovarian cancer G-protein-coupled receptor 1 (OGR1) and GPR4 have recently been identified as proton-sensing or extracellular pHresponsive G-protein-coupled receptors stimulating inositol phosphate production and cAMP accumulation, respectively. In the present study, we found that OGR1 and GPR4 mRNAs were expressed in human aortic smooth muscle cells (AoSMCs). Acidic extracellular pH induced inositol phosphate production, a transient increase in intracellular Ca2+ concentration ([Ca2+]i), and cAMP accumulation in these cells. When small interfering RNAs (siRNAs) targeted for OGR1 and GPR4 were transfected to the cells, the acidinduced inositol phosphate production and [Ca2+]i increase were markedly inhibited by the OGR1 siRNA but not by the GPR4 siRNA. Unexpectedly, the acid-induced cAMP accumulation was also largely inhibited by OGR1 siRNA but only slightly by GPR4 siRNA. Acidic extracellular pH also stimulated prostaglandin I2 (PGI2) production, which was again inhibited by OGR1 siRNA. The specific inhibitors for extracellular signal-regulated kinase kinase and cyclooxygenase attenuated the acid-induced PGI2 production and cAMP accumulation without changes in the inositol phosphate production. A specific inhibitor of phospholipase C also inhibited the acid-induced cAMP accumulation. In conclusion, OGR1 is a major receptor involved in the extracellular acid-induced stimulation of PGI2 production and cAMP accumulation in AoSMCs. The cAMP accumulation may occur through OGR1-mediated stimulation of the phospholipase C/cyclooxygenase/PGI2 pathway.