Protein phosphorylation involved in the gene expression of the hydrogen sulphide producing enzyme cystathionine γ-lyase in the pancreatic β-cell

► CSE is an inducible enzyme that produces the gasomessenger H2S in pancreatic β-cells. ► Induction of CSE is dependent on an increase in intracellular Ca2+. ► Protein phosphorylation by CaMK II and ERK is involved in CSE expression. ► Two ERK-phosphorylatable transcription factors, Sp1 and Elk1, regulate CSE expression. Cystathionine γ-lyase (CSE) is one of the major enzymes for the production of hydrogen sulphide (H2S), a multifunctional gasotransmitter in the pancreatic β-cell. We examined the mechanisms by which glucose induces CSE expression in mouse pancreatic islets and the insulin-secreting cell line MIN6. CSE expression was increased by anti-diabetic sulphonylureas, and decreased by the ATP-sensitive K+-channel opener diazoxide and the voltage-dependent Ca2+ channel blocker nitrendipine. Application of the synthetic inhibitors of protein kinases revealed the involvement of Ca2+/calmodulin-dependent protein kinase (CaMK) II and extracellular signal-regulated protein kinase (ERK) in glucose- and thapsigargin-induced CSE expression. The CaMK IIδ knockdown also suppressed CSE expression. Knockdown of the transcription factors Sp1 and Elk1, both of which can be phosphorylated by ERK, blunted CSE expression. By a reporter assay, we found Sp1 may directly and Elk1 may indirectly regulate CSE expression. These findings suggest Ca2+-dependent CSE expression may be mediated via protein phosphorylation of Sp1 and Elk1 in pancreatic β-cells.