A Single Amino Acid Mutation (R104P) in the E/DRY Motif of GPR40 Impairs Receptor Function
文献类型：期刊论文
| 作者 | Guo, Shimeng1,3; Zhang, Jiandong2,3; Zhang, Shuyong3; Li, Jing3
|
| 刊名 | PLOS ONE
 |
| 出版日期 | 2015-10-27 |
| 卷号 | 10期号:10 |
| ISSN号 | 1932-6203 |
| DOI | 10.1371/journal.pone.0141303 |
| 文献子类 | Article |
| 英文摘要 | Type 2 Diabetes Mellitus with insulin resistance, pancreatic beta cell dysfunction, and hepatic glucose overproduction is increasing in epidemic proportions worldwide. G protein-coupled receptor 40 (GPR40), a clinically proven anti-diabetic drug target, is mainly expressed in pancreatic beta cells and insulin-secreting cell lines. Long chain fatty acids (LCFA) increase intracellular calcium concentration and amplify glucose-stimulated insulin secretion by activating GPR40. Here we report that the arginine 104 (R104) is critical for the normal function of GPR40. Mutation of R104 to Proline (R104P) results in complete loss of the receptor function. Linoleic acid, ligand of GPR40, could not elicit calcium increase and ERK phosphorylation in cells expressing this mutant receptor. Further study indicated the R104P mutation reduces cell surface localization of GPR40 without affecting the expression of the protein. The small portion of GPR40 R104P mutant that is still located on the membrane has no physiological function, and does not internalize in response to linoleic acid stimulation. These data demonstrate that R104 in GPR40 is critically involved in the normal receptor functions. Interestingly, R104P is a registered single-nucleotide polymorphism of GPR40. The relationship of this GPR40 variant and type 2 diabetes warrants further investigation. |
| WOS关键词 | PROTEIN-COUPLED RECEPTORS ; FREE FATTY-ACIDS ; STIMULATED INSULIN-SECRETION ; SMALL-MOLECULE AGONISTS ; M1 MUSCARINIC RECEPTOR ; PANCREATIC BETA-CELLS ; DRY MOTIF ; ARGININE ; GENE ; IDENTIFICATION |
| 资助项目 | National Natural Sciences Foundation of China[81202341] ; 973 programme[2014CB541906] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program"[2014ZX09507-002] ; Shanghai Commission of Science and Technology[15ZR1408200] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:000363804200045 |
| 出版者 | PUBLIC LIBRARY SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276352]  |
| 专题 | 国家新药筛选中心 |
| 通讯作者 | Zhang, Shuyong |
| 作者单位 | 1.Shanghai Univ, Sch Life Sci, Shanghai, Peoples R China; 2.Nanchang Univ, Coll Pharm, Nanchang, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Natl Ctr Drug Screening, Shanghai 200031, Peoples R China |
| 推荐引用方式 GB/T 7714 | Guo, Shimeng,Zhang, Jiandong,Zhang, Shuyong,et al. A Single Amino Acid Mutation (R104P) in the E/DRY Motif of GPR40 Impairs Receptor Function[J]. PLOS ONE,2015,10(10). |
| APA | Guo, Shimeng,Zhang, Jiandong,Zhang, Shuyong,&Li, Jing.(2015).A Single Amino Acid Mutation (R104P) in the E/DRY Motif of GPR40 Impairs Receptor Function.PLOS ONE,10(10). |
| MLA | Guo, Shimeng,et al."A Single Amino Acid Mutation (R104P) in the E/DRY Motif of GPR40 Impairs Receptor Function".PLOS ONE 10.10(2015). |
入库方式： OAI收割
来源：上海药物研究所
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