The CD38-cyclic ADP-ribose signaling system in insulin secretion

Glucose induces an increase in the intracellular Ca²⁺ concentration in pancreatic β-cells to secrete insulin. CD38 occurs in β-cells and has both ADP-ribosyl cyclase, which catalyzes the formation of cyclic ADP-ribose (cADPR) from NAD⁺, and cADPR hydrolase, which converts cADPR to ADP-ribose. ATP, produced by glucose metabolism, competes with cADPR for the binding site, Lys-129, of CD38, resulting in the inhibition of the hydrolysis of cADPR and thereby causing cADPR accumulation in β-cells. Cyclic ADP-ribose then binds to FK506-binding protein 12.6 is the ryanodine receptor Ca²⁺ channel (RyR), dissociating the binding protein from RyR to induce the release of Ca²⁺ from the endoplasmic reticulum. Ca²⁺/calmodulin-dependent protein kinase II (CaM kinase II) phosphorylates RyR to sensitize and activate the Ca²⁺ channel. Ca²⁺, released from the RyR, further activates CaM kinase II and amplifies the process. Thus, cADPR acts as a second messenger for Ca²⁺ mobilization to secrete insulin. The novel mechanism of insulin secretion described above is different from the conventional hypothesis in which Ca²⁺ influx from extracellular sources plays a role in insulin secretion by glucose.