Abstract
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 in 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.
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References
Ashcroft FM, Ashcroft SJH: Insulin - Molecular Biology to Pathology. Oxford University Press, Oxford, 1992, pp 97–150
Takasawa S, Nata K, Yonekura H, Okamoto H: Cyclic ADP-ribose in insulin secretion from pancreatic β cells. Science 259: 370–373, 1993
Takasawa S, Tohgo A, Noguchi N, Koguma T, Nata K, Sugimoto T, Yonekura H, Okamoto H: Synthesis and hydrolysis of cyclic ADP-ribose by human leukocyte antigen CD38 and inhibition of the hydrolysis by ATP. J Biol Chem 268: 26052–26054, 1993
Okamoto H, Takasawa S, Tohgo A: New aspects of the physiological significance of NAD, poly ADP-ribose and cyclic ADP-ribose. Biochimie 77: 356–363, 1995
Kato I, Takasawa S, Akabane A, Tanaka O, Abe H, Takamura T, Suzuki Y, Nata K, Yonekura H, Yoshimoto T, Okamoto H: Regulatory role of CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) in insulin secretion by glucose in pancreatic β cells: Enhanced insulin secretion in CD38 transgenic mice. J Biol Chem 270: 30045–30050, 1995
Okamoto H, Takasawa S, Tohgo A, Nata K, Kato I, Noguchi N: Synthesis and hydrolysis of cyclic ADP-ribose by human leukocyte antigen CD38: Inhibition of hydrolysis by ATP and the physiological significance. Meth Enzymol 280: 306–318, 1997
Takahashi K, Kukimoto I, Tokita K, Inageda K, Inoue S, Kontani K, Hoshino S, Nishina H, Kanaho Y, Katada T: Accumulation of cyclic ADP-ribose measured by a specific radioimmunoassay in differentiated human leukemic HL-60 cells with all-trans-retinoic acid. FEBS Lett 371: 204–208, 1995
Takasawa S, Akiyama T, Nata K, Kuroki M, Tohgo A, Noguchi N, Kobayashi S, Kato I, Katada T, Okamoto H: Cyclic ADP-ribose and inositol 1,4,5–trisphosphate as alternate second messenger for intracellular Ca2+ mobilization in normal and diabetic β-cells. J Biol Chem 273: 2497–2500, 1998
Tohgo A, Munakata H, Takasawa S, Nata K, Akiyama T, Hayashi N, Okarnoto H: Lysine 129 of CD38 (ADP-ribosyl cyclase/cyclic ADPribose hydrolase) participates in the binding of ATP to inhibit the cyclic ADP-ribose hydrolase. J Biol Chem 272: 3879–3882, 1997
Tohgo A, Takasawa S, Noguchi N, Koguma T, Nata K, Sugimoto T, Furuya Y, Yonekura H, Okamoto H: Essential cysteine residues for cyclic ADP-ribose synthesis and hydrolysis by CD38. J Biol Chem 269: 28555–28557, 1994
Nata K, Takamura T, Karasawa T, Kumagai T, Hashioka W, Tohgo A, Yonekura H, Takasawa S, Nakamura S, Okamoto H: Human gene encoding CD38 (ADP-riboseyl cyclase/cyclic ADP-ribose hydrolase): Organization, nucleotide sequence and alternative splicing. Gene 186: 285–292, 1997
Yagui K, Shimada F, Miura M, Hashimoto N, Suzuki Y, Tokoyama Y, Nata K, Tohgo A, Ikehata F, Takasawa S, Okamoto H, Makino H, Saito Y, Kanatsuka A: A missense mutation in the CD38 gene, a novel factor for insulin secretion: Association with Type II diabetes mellitus in Japanese subjects and evidence of abnormal function when expressed in vitro. Diabetologia 1998 (in press)
Hua S-Y, Tokimasa T, Takasawa T, Furuya Y, Nohmi M, Okamoto H, Kuba K: Cyclic ADP-ribose modulates Ca2+ release channels for activation by physiological Ca2+ entry in bullfrog sympathetic neurons. Neuron 12: 1073–1079, 1994
Ebihara S, Sasaki T, Hida W, Kikuchi Y, Oshiro T, Shimura S, Takasawa S, Okamoto H, Nishiyama A, Akaike N, Shirato K: Role of cyclic ADP-ribose in ATP-activated potassium currents in alveolar macrophages. J Biol Chem 272: 16023–16029, 1997
Noguchi N, Takasawa S, Nata K, Tohgo A, Kato I, Ikehata F, Yonekura H, Okamoto H: Cyclic ADP-ribose binds to FK506–binding protein 12.6 to release Ca2+ from islet microsomes. J Biol Chem 272: 3133–3136, 1997
Takasawa S, Ishida A, Nata K, Nakagawa K, Noguchi N, Tohgo A, Kato I, Yonekura H, Fujisawa H, Okamoto H: Requirement of calmodulindependent protein kinase II in cyclic ADP-ribose-mediated intracellular Ca2+ mobilization. J Biol Chem 270: 30257–30259, 1995
Berridge MJ, Irvine RF: Inositol phosphates and cell signalling. Nature 341: 197–205, 1989
Okamoto H, Takasawa S, Nata K: The CD38–cyclic ADP-ribose signalling system in insulin secretion: Molecular basis and clinical implications. Diabetologia 40: 1485–1491, 1997
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Okamoto, H. The CD38-cyclic ADP-ribose signaling system in insulin secretion. Mol Cell Biochem 193, 115–118 (1999). https://doi.org/10.1023/A:1006980630912
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DOI: https://doi.org/10.1023/A:1006980630912