Ca2+ signaling and gene transcription in glucose-stimulated insulinoma cells

Glucose stimulation induces expression of the transcription factors Egr-1 and c-Jun as well as phosphorylation of CREB and c-Jun in insulinoma cells. The activator protein-1 (AP-1) binding sites within the c-Jun promoter, the serum response elements (SREs) within the Egr-1 promoter, and cyclic AMP response elements (CREs) function as glucose responsive element. Glucose-induced transcriptional regulation was attenuated by inhibition of L-type Ca2+ channels, or chelating cytoplasmic Ca2+. It has been proposed that a rise in nuclear Ca2+ is required for CREB-mediated transcription of CRE-regulated genes, while elevated cytoplasmic Ca2+ levels trigger an upregulation of SRE-containing genes. Here, we show that a rise in cytoplasmic Ca2+ is required for AP-1, CRE, and SRE mediated transcription in glucose-stimulated insulinoma cells. Buffering Ca2+ in the nucleus or the endoplasmic reticulum had no inhibitory effect upon transcription. However, overexpression of the mitochondrial protein Fis-1 or inhibition of the GTPase Drp-1 impaired glucose-stimulated gene transcription in insulinoma cells, suggesting that the mitochondria play an important role in regulating Ca2+ mediated gene transcription. The extracellular signal-regulated protein kinase functions as an essential link connecting glucose stimulation, the rise in cytoplasmic Ca2+, and enhanced transcription in insulinoma cells.