'The CD38-cyclic ADP-ribose-signal system': Molecular mechanism and biological significance

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Glucose induces an increase in the intracellular Ca2+ concentration in pancreatic β-cells to secrete insulin. CD38 exists 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. CADPR then binds to FK506-binding protein 12.6 (FKBP12.6) in the islet type of the ryanodine receptor (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 this 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. Furthermore, many physiological and pathological phenomena in various tissues and cells such as cardiac muscles, cerebellum, neuronal cells, pancreatic acinar cells, alveolar macrophages and immune B-cells become understandable in terms of 'the CD38-cADPR signaling system' that sometimes acts in cooperation with other signal systems.

Original languageEnglish
Pages (from-to)131-139
Number of pages9
JournalFolia Pharmacologica Japonica
Issue number3
Publication statusPublished - 1999


  • CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase)
  • Cyclic ADP-ribose
  • Insulin secretion
  • Intracellular Ca mobilization
  • Ryanodine receptor


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