Department of Clinical Science, SUS, Division of Islet Cell Physiology, University of Lund, Jan Waldenströmsgata 35, Building 91, Floor 11, SE-205 02, Malmö, Sweden.
Experimental cardiovascular research, University of Lund, Lund, Sweden.
Pflugers Arch. 2019 Apr;471(4):633-645. doi: 10.1007/s00424-019-02262-7. Epub 2019 Feb 15.
We have recently shown that the G protein-coupled receptor 142 (GPR142) is expressed in both rodent and human pancreatic β-cells. Herein, we investigated the cellular distribution of GPR142 within islets and the effects of selective agonists of GPR142 on glucose-stimulated insulin secretion (GSIS) in the mouse islets and INS-1832/13 cells. Double-immunostaining revealed that GPR142 immunoreactivity in islets mainly occurs in insulin-positive cells. Potentiation of GSIS by GPR142 activation was accompanied by increased cAMP content in INS-1832/13 cells. PKA/Epac inhibition markedly suppressed the effect of GPR142 activation on insulin release. Gpr142 knockdown (Gpr142-KD) in islets was accompanied by elevated release of MCP-1, IFNγ, and TNFα during culture period and abolished the modulatory effect of GPR142 activation on the GSIS. Gpr142-KD had no effect on Ffar1, Ffar2, or Ffar3 mRNA while reducing Gpr56 and increasing Tlr5 and Tlr7 mRNA expression. Gpr142-KD was associated with an increased expression of Chrebp, Txnip, RhoA, and mitochondrial Vdac1 concomitant with a reduced Pdx1, Pax6, and mitochondrial Vdac2 mRNA levels. Long-term exposure of INS-1832/13 cells to hyperglycemia reduced Gpr142 and Vdac2 while increased Chrebp, Txnip, and Vdac1 mRNA expression. GPR142 agonists or Bt-cAMP counteracted this effect. Glucotoxicity-induced decrease of cell viability in Gpr142-KD INS-1 cells was not affected by GPR142-agonists while Bt-cAMP prevented it. The results show the importance of Gpr142 in the maintenance of pancreatic β-cell function in rodents and that GPR142 agonists potentiate GSIS by an action, which most likely is due to increased cellular generation of second messenger molecule cAMP.
我们最近表明，G 蛋白偶联受体 142（GPR142）在啮齿动物和人类胰岛β细胞中均有表达。在此，我们研究了 GPR142 在胰岛中的细胞分布，以及 GPR142 选择性激动剂对小鼠胰岛和 INS-1832/13 细胞葡萄糖刺激的胰岛素分泌（GSIS）的影响。双重免疫染色显示，胰岛中的 GPR142 免疫反应主要发生在胰岛素阳性细胞中。GPR142 激活增强 GSIS 的同时，也增加了 INS-1832/13 细胞中的 cAMP 含量。PKA/Epac 抑制显著抑制了 GPR142 激活对胰岛素释放的影响。胰岛中的 Gpr142 敲低（Gpr142-KD）伴随着培养期间 MCP-1、IFNγ和 TNFα的释放增加，并消除了 GPR142 激活对 GSIS 的调节作用。Gpr142-KD 对 Ffar1、Ffar2 或 Ffar3 mRNA 没有影响，而降低了 Gpr56 并增加了 Tlr5 和 Tlr7 mRNA 的表达。Gpr142-KD 与 Chrebp、Txnip、RhoA 和线粒体 Vdac1 的表达增加有关，同时 Pdx1、Pax6 和线粒体 Vdac2 mRNA 水平降低。长期暴露于高血糖会降低 INS-1832/13 细胞中的 Gpr142 和 Vdac2，同时增加 Chrebp、Txnip 和 Vdac1 mRNA 的表达。GPR142 激动剂或 Bt-cAMP 对抗了这种作用。Gpr142-KD INS-1 细胞的糖毒性诱导的细胞活力下降不受 GPR142 激动剂的影响，而 Bt-cAMP 则可防止其发生。结果表明，Gpr142 在维持啮齿动物胰岛β细胞功能方面具有重要意义，GPR142 激动剂通过增加第二信使分子 cAMP 的细胞生成来增强 GSIS。
