High resolution

Module 7: Figure α-cell signalling

Control of glucagon release and biosynthesis by glucagon-secreting α-cells.

Membrane depolarization opens L-type Ca2+ channels that introduce Ca2+ into the cell, which is responsible for both glucagon release and biosynthesis. The immediate effect is to stimulate the exocytosis of vesicles containing glucagon. The longer-term changes in biosynthesis depend upon Ca2+ activation of glucagon gene transcription. It activates the calcineurin (CaN)/nuclear factor of activated T cells (NFAT) transcription cascade. The dephosphorylated NFAT that enters the nucleus combines with hepatocyte nuclear factor 3β (HNF3β) to bind to a G2 site. In addition, Ca2+ enters the nucleus to activate Ca2+/calmodulin-dependent protein kinase IV (CaMKIV), which phosphorylates cyclic AMP response element-binding protein (CREB). The latter is also activated by hormonal inputs operating through cyclic AMP, and this co-operation between the Ca2+ and cyclic AMP pathways enables the cell to regulate biosynthesis through multiple inputs.