The CD38-cyclic ADP-ribose signal system, a paradigm for Ca²⁺-signaling

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In 1993, we found that an NAD⁺ metabolite, cyclic ADP-ribose (cADPR), is a second messenger for Ca²⁺ mobilization for insulin secretion in pancreatic beta-cells and proposed the CD38-cADPR signal system for insulin secretion by glucose. We demonstrated that CD38, originally identified as a cell surface marker of lymphocyte differentiation, has both ADP-ribosyl cyclase and cADPR hydrolase activities and that ATP, produced by glucose metabolism, competes with cADPR for the binding site, Lys-129, of CD38, resulting in the inhibition of cADPR hydrolysis and thereby causing cADPR accumulation in beta-cells. cADPR then binds to the FK506-binding protein 12.6 (FKBP12.6 or calstatin 2) in the ryanodine receptor (RyR), dissociating the binding protein from RyR to release Ca²⁺ from the endoplasmic reticulum. Thus, cADPR acts as a second messenger for Ca²⁺ mobilization to secrete insulin in response to glucose stimulation. To confirm the hypothesis, we produced CD38 knockout mice by homologous recombination and demonstrated that CD38 disruption impairs the glucose-induced increases in cADPR, intracellular Ca²⁺ concentration, and insulin secretion. We also produced FKBP12.6 knockout mice and the mice showed impaired insulin secretion by glucose stimulation in vitro and in vivo. Recently, various physiological phenomena from animal to plant cells, in addition to those of pancreatic beta-cells, become understandable in terms of the CD38-cADPR signal system for Ca²⁺ mobilization. [Jpn J Physiol 54 Suppl:S17 (2004)]