Regulation and function of AP-1 in insulinoma cells and pancreatic β-cells.

Ca1.2 L-type voltage-gated Ca channels play a central role in pancreatic β-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 Ca1.2 Ca channels and addressed the function of the transcription factor activator protein-1 (AP-1) in pancreatic β-cells of transgenic mice. Stimulation of Ca1.2 Ca channels activates AP-1 in insulinoma cells. Pharmacological and genetic experiments identified c-Jun N-terminal protein kinase as a signal transducer connecting Ca1.2 Ca 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 β-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 Ca1.2 Ca 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 β-cells in vivo, the regulation of glucose homeostasis.