Each one of certain histidine residues in G-protein-coupled receptor GPR4 is critical for extracellular proton-induced stimulation of multiple G-protein-signaling pathways
Each one of certain histidine residues in G-protein-coupled receptor GPR4 is critical for extracellular proton-induced stimulation of multiple G-protein-signaling pathways
复制标题
DOI：
10.1016/j.phrs.2010.02.013
复制
发表时间：
2010-06-01
影响因子：
9.3
通讯作者：
Okajima, Fumikazu
中科院分区：
文献类型：
--
作者：
Liu, Jin-Peng;Nakakura, Takashi;Okajima, Fumikazu
GPR4，先前被认为是鞘酰基磷胆碱的受体，最近被确定为质子传感G蛋白偶联受体，偶联多种细胞内信号通路，包括G(s)-蛋白/cAMP， G(12/13)-蛋白/Rho和G(q)-蛋白/磷脂酶C途径。在本研究中，我们研究了位于细胞外的GPR4组氨酸残基是否感知细胞外质子，如果是，某个组氨酸残基是否对单个或多个信号通路的偶联至关重要。我们发现，GPR4 n端79,165或269处组氨酸残基向苯丙氨酸的突变使质子诱导的信号活性的半最大有效浓度（EC50）向右移动，包括cAMP积累，反映Rho活性的SRE启动子活性和反映磷脂酶C信号活性的NFAT启动子活性，而最大活性没有明显变化。这些结果表明，GPR4中79,165和269个组氨酸残基的质子化可能是受体构象变化的关键，从而通过g蛋白偶联多种细胞内信号通路。(C) 2010 Elsevier Ltd.版权所有。
GPR4, previously proposed as the receptor for sphingosylphosphorylcholine, has recently been identified as the proton-sensing G-protein-coupled receptor coupling to multiple intracellular signaling pathways, including the G(s)-protein/cAMP, G(12/13)-protein/Rho, and G(q)-protein/phospholipase C pathways. In the present study, we examined whether extracellularly located histidine residues of GPR4 sense extracellular protons and, if so, whether a certain histidine residue is critical for coupling to the single or multiple signaling pathway(s). We found that the mutation of histidine residue at 79,165, or 269 from the N-terminal of GPR4 to phenylalanine shifted the half-maximal effective concentration (EC50) of proton-induced signaling activities to the right, including cAMP accumulation, SRE promoter activity reflecting Rho activity, and NFAT promoter activity reflecting phospholipase C signaling activity, without an appreciable change in the maximal activities. These results suggest that the protonation of each one of histidine residues at 79,165, and 269 in GPR4 may be critical for conformational change of the receptor for coupling to multiple intracellular signaling pathways through G-proteins. (C) 2010 Elsevier Ltd. All rights reserved.