Regulation of intracellular Ca2+ stores by multiple Ca2+-releasing messengers

Although glucose-elicited insulin secretion depends on Ca(2+) entry through voltage-gated Ca(2+) channels in the surface cell membrane of the pancreatic beta-cell, there is also ample evidence for an important role of intracellular Ca(2+) stores, particularly in relation to hormone- or neurotransmitter-induced insulin secretion. There is now direct evidence for Ca(2+) entry-induced release of Ca(2+) from the endoplasmic reticulum in neurons, but with regard to glucose stimulation of beta-cells, there is conflicting evidence about the operation of such a process. This finding suggests that the sensitivity of the Ca(2+) release channels in the endoplasmic reticulum membrane varies under different conditions and therefore is regulated. Recent evidence from studies of pancreatic acinar cells has revealed combinatorial roles of multiple messengers in setting the sensitivity of the endoplasmic reticulum for Ca(2+) release. Here we focus on the possible combinatorial roles of inositol 1,4,5-trisphosphate, cyclic ADP-ribose, and nicotinic acid adenine dinucleotide phosphate in beta-cell function.