Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors
Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors
复制标题
DOI：
10.1038/nature02488
复制
发表时间：
2004-05-13
期刊：
影响因子：
64.8
通讯作者：
Ling, L
中科院分区：
文献类型：
--
作者：
He, WH;Miao, FJP;Ling, L
柠檬酸循环是调节能量稳态和细胞代谢的核心（1）。催化柠檬酸循环步骤的酶的突变导致具有各种临床表现的人类疾病（2）。柠檬酸循环的中间产物以微摩尔浓度存在于血液中，并受呼吸、代谢和肾重吸收/排出的调节。在这里，我们表明GPR 91（参考文献3），以前的孤儿G蛋白偶联受体（GPCR），作为柠檬酸循环中间体琥珀酸的受体。我们还报道了GPR 91的近亲GPR 99（参考文献4）对柠檬酸循环中的另一个中间体α-酮戊二酸有反应。因此，通过充当GPCR的配体，发现琥珀酸和α-酮戊二酸具有超出其传统作用的意想不到的信号传导功能。此外，我们发现琥珀酸盐会增加动物的血压。琥珀酸诱导的高血压效应涉及肾素-血管紧张素系统，并在GPR 91缺陷小鼠中被消除。我们的研究结果表明GPR 91在肾血管性高血压中可能发挥作用，肾血管性高血压是一种与动脉粥样硬化、糖尿病和肾衰竭密切相关的疾病（5，6）。
The citric acid cycle is central to the regulation of energy homeostasis and cell metabolism(1). Mutations in enzymes that catalyse steps in the citric acid cycle result in human diseases with various clinical presentations(2). The intermediates of the citric acid cycle are present at micromolar concentration in blood and are regulated by respiration, metabolism and renal reabsorption/ extrusion. Here we show that GPR91 (ref. 3), a previously orphan G-protein-coupled receptor (GPCR), functions as a receptor for the citric acid cycle intermediate succinate. We also report that GPR99 (ref. 4), a close relative of GPR91, responds to alpha-ketoglutarate, another intermediate in the citric acid cycle. Thus by acting as ligands for GPCRs, succinate and alpha-ketoglutarate are found to have unexpected signalling functions beyond their traditional roles. Furthermore, we show that succinate increases blood pressure in animals. The succinate-induced hypertensive effect involves the renin - angiotensin system and is abolished in GPR91-deficient mice. Our results indicate a possible role for GPR91 in renovascular hypertension, a disease closely linked to atherosclerosis, diabetes and renal failure(5,6).