Fehmann H C, Jiang J, Pitt D, Schweinfurth J, Göke B
Department of Medicine, Philipps-University of Marburg, Germany.
Pancreas. 1996 Oct;13(3):273-82. doi: 10.1097/00006676-199610000-00010.
Glucagon-like peptide-I (GLP-I) is a potent incretin hormone and mediates its actions via the cyclic AMP (cAMP) pathway. The GLP-I receptor belongs to the family of seven-transmembrane domain receptors coupled to G proteins. We have analyzed the regulation of GLP-I receptor function and expression by its own ligand and the cAMP-dependent pathway in rat insulinoma-derived beta cells (RINm5F). The GLP-I receptor underwent rapid homologous desensitization, which occurred at the receptor level. This was characterized by a reduced binding capacity not mediated by protein kinase A (PKA). GLP-I receptor mRNA levels were down-regulated during incubation of cells by agents increasing cAMP levels including GLP-I itself. This effect was dependent upon time and concentration. Forskolin, the PKA activator 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole-3, 5-monophosphorothiotate, and GLP-I stabilized the GLP-I receptor mRNA. All induced down-regulation of the GLP-I receptor number within 3 h, a time point at which GLP-I receptor mRNA levels were not decreased. This effect was not influenced by cycloheximide. Therefore, in addition to transcriptional effects, posttranslational mechanisms exist to regulate GLP-I receptor numbers in insulin-secreting cells.
胰高血糖素样肽-1（GLP-1）是一种强效的肠促胰岛素激素，通过环磷酸腺苷（cAMP）途径介导其作用。GLP-1受体属于与G蛋白偶联的七跨膜结构域受体家族。我们分析了大鼠胰岛素瘤来源的β细胞（RINm5F）中其自身配体和cAMP依赖性途径对GLP-1受体功能和表达的调节。GLP-1受体经历了快速同源脱敏，这发生在受体水平。其特征是结合能力降低，这不是由蛋白激酶A（PKA）介导的。在细胞培养过程中，包括GLP-1本身在内的增加cAMP水平的试剂会使GLP-1受体mRNA水平下调。这种效应取决于时间和浓度。福斯高林、PKA激活剂5,6-二氯-1-β-D-呋喃核糖基苯并咪唑-3,5-单磷酸硫代酸盐和GLP-1可稳定GLP-1受体mRNA。所有这些在3小时内都会导致GLP-1受体数量下调，而此时GLP-1受体mRNA水平并未降低。这种效应不受放线菌酮的影响。因此，除了转录效应外，还存在翻译后机制来调节胰岛素分泌细胞中GLP-1受体的数量。
