| First Author | Backes TM | Year | 2021 |
| Journal | Biochem Pharmacol | Volume | 193 |
| Pages | 114748 | PubMed ID | 34461116 |
| Mgi Jnum | J:318718 | Mgi Id | MGI:6850345 |
| Doi | 10.1016/j.bcp.2021.114748 | Citation | Backes TM, et al. (2021) Regulation and function of AP-1 in insulinoma cells and pancreatic beta-cells. Biochem Pharmacol 193:114748 |
| abstractText | Cav1.2 L-type voltage-gated Ca(2+) channels play a central role in pancreatic beta-cells by integrating extracellular signals with intracellular signaling events leading to insulin secretion and altered gene transcription. Here, we investigated the intracellular signaling pathway following stimulation of Cav1.2 Ca(2+) channels and addressed the function of the transcription factor activator protein-1 (AP-1) in pancreatic beta-cells of transgenic mice. Stimulation of Cav1.2 Ca(2+) channels activates AP-1 in insulinoma cells. Pharmacological and genetic experiments identified c-Jun N-terminal protein kinase as a signal transducer connecting Cav1.2 Ca(2+) channel activation with gene transcription. Moreover, the basic region-leucine zipper proteins ATF2 and c-Jun or c-Jun-related proteins were involved in stimulus-transcription coupling. We addressed the functions of AP-1 in pancreatic beta-cells analyzing a newly generated transgenic mouse model. These transgenic mice expressed A-Fos, a mutant of c-Fos that attenuates DNA binding of c-Fos dimerization partners. In insulinoma cells, A-Fos completely blocked AP-1 activation following stimulation of Cav1.2 Ca(2+) channels. The analysis of transgenic A-Fos-expressing mice revealed that the animals displayed impaired glucose tolerance. Thus, we show here for the first time that AP-1 controls an important function of pancreatic beta-cells in vivo, the regulation of glucose homeostasis. |
