Institut Cochin, INSERM U1016, CNRS UMR 8104, Université de Paris, 123 bd du Port-Royal, 75014, Paris, France.
Assistance Publique Hôpitaux de Paris, Cell Therapy Unit, Saint Louis Hospital, 75010, Paris, France.
Sci Rep. 2020 Aug 10;10(1):13469. doi: 10.1038/s41598-020-69758-6.
G protein-coupled receptors are seven transmembrane signaling molecules that are involved in a wide variety of physiological processes. They constitute a large protein family of receptors with almost 300 members detected in human pancreatic islet preparations. However, the functional role of these receptors in pancreatic islets is unknown in most cases. We generated a new stable human beta cell line from neonatal pancreas. This cell line, named ECN90 expresses both subunits (GABBR1 and GABBR2) of the metabotropic GABA receptor compared to human islet. In ECN90 cells, baclofen, a specific GABA receptor agonist, inhibits cAMP signaling causing decreased expression of beta cell-specific genes such as MAFA and PCSK1, and reduced insulin secretion. We next demonstrated that in primary human islets, GABBR2 mRNA expression is strongly induced under cAMP signaling, while GABBR1 mRNA is constitutively expressed. We also found that induction and activation of the GABA receptor in human islets modulates insulin secretion.
G 蛋白偶联受体是一种七跨膜信号分子，参与多种生理过程。它们构成了一个庞大的受体蛋白家族，在人类胰岛制剂中检测到近 300 个成员。然而，在大多数情况下，这些受体在胰岛中的功能作用尚不清楚。我们从新生儿胰腺中产生了一种新的稳定的人类β细胞系。与人类胰岛相比，这种细胞系命名为 ECN90，表达代谢型 GABA 受体的两个亚基（GABBR1 和 GABBR2）。在 ECN90 细胞中，GABA 受体的特异性激动剂巴氯芬抑制 cAMP 信号转导，导致β细胞特异性基因如 MAFA 和 PCSK1 的表达减少，胰岛素分泌减少。接下来，我们证明在原代人胰岛中，GABBR2mRNA 的表达在 cAMP 信号转导下强烈诱导，而 GABBR1mRNA 则持续表达。我们还发现，GABA 受体在人胰岛中的诱导和激活调节胰岛素分泌。
