The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids
The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids
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DOI：
10.1074/jbc.m211609200
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发表时间：
2003-03-28
影响因子：
4.8
通讯作者：
Dowell, SJ
中科院分区：
文献类型：
--
作者：
Brown, AJ;Goldsworthy, SM;Dowell, SJ
GPR 41和GPR 43是孤儿G蛋白偶联受体同源家族的相关成员，其在人和小鼠中均在单个染色体基因座串联编码。我们在酵母中的常规配体库筛选期间鉴定乙酸根阴离子为人GPR 43的激动剂。在使用Ca 2+动员和[S-35]鸟苷5 '-O-（3-硫代三磷酸）结合试验将GPR 43瞬时转染到哺乳动物细胞中后，并通过与非洲爪蟾卵母细胞中GIRK G蛋白调节的钾通道共表达，证实了这种活性。其他短链羧酸阴离子如甲酸根、丙酸根、丁酸根和戊酸根也具有激动剂活性。GPR 41与GPR 43相关（52%相似性; 43%同一性），并被相似的配体激活，但对碳链长度具有不同的特异性，其中戊酸是最有效的激动剂。第三个家族成员，GPR 42，最有可能是GPR 41的最近基因重复，可能是假基因。GPR 41主要在脂肪组织中表达，而最高水平的GPR 43在免疫细胞中发现。这些受体的同源生理配体的身份尚不清楚，尽管已知丙酸盐在某些病理生理条件下以高浓度在体内发生。
GPR41 and GPR43 are related members of a homologous family of orphan G protein-coupled receptors that are tandemly encoded at a single chromosomal locus in both humans and mice. We identified the acetate anion as an agonist of human GPR43 during routine ligand bank screening in yeast. This activity was confirmed after transient transfection of GPR43 into mammalian cells using Ca2+ mobilization and [S-35]guanosine 5'-O-(3-thiotriphosphate) binding assays and by coexpression with GIRK G protein-regulated potassium channels in Xenopus laevis oocytes. Other short chain carboxylic acid anions such as formate, propionate, butyrate, and pentanoate also had agonist activity. GPR41 is related to GPR43 (52% similarity; 43% identity) and was activated by similar ligands but with differing specificity for carbon chain length, with pentanoate being the most potent agonist. A third family member, GPR42, is most likely a recent gene duplication of GPR41 and may be a pseudogene. GPR41 was expressed primarily in adipose tissue, whereas the highest levels of GPR43 were found in immune cells. The identity of the cognate physiological ligands for these receptors is not clear, although propionate is known to occur in vivo at high concentrations under certain pathophysiological conditions.