Regulatory role of CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) in insulin secretion by glucose in pancreatic beta cells. Enhanced insulin secretion in CD38-expressing transgenic mice

• Published in: The Journal of biological chemistry Vol. 270; no. 50; pp. 30045 - 30050
• Main Authors: Kato, I, Takasawa, S, Akabane, A, Tanaka, O, Abe, H, Takamura, T, Suzuki, Y, Nata, K, Yonekura, H, Yoshimoto, T
• Format: Journal Article
• Language: English
• Published: United States 15.12.1995
• Subjects: actividad enzimatica; activite enzymatique; Adenosine Diphosphate Ribose - analogs & derivatives; Adenosine Diphosphate Ribose - metabolism; adenosine triphosphate; Adenosine Triphosphate - pharmacology; adenosintrifosfato; adn; adn recombinado; adn recombine; ADP-ribosyl Cyclase; ADP-ribosyl Cyclase 1; animal transgenique; animales transgenicos; Animals; Antigens, CD - drug effects; Antigens, CD - genetics; Antigens, CD - metabolism; Antigens, Differentiation - drug effects; Antigens, Differentiation - genetics; Antigens, Differentiation - metabolism; arn mensajero; arn messager; azucar en sangre; blood sugar; calcio; calcium; cation; cationes; cations; Cyclic ADP-Ribose; dna; enzimas; enzyme; enzymes; enzymic activity; expresion genica; expression des genes; gene expression; gene transfer; glucosa; glucose; Glucose - pharmacology; hidrolasas; hombres; homme; Humans; hydrolase; hydrolases; In Vitro Techniques; insulin; Insulin - biosynthesis; Insulin - genetics; Insulin - metabolism; Insulin Secretion; insulina; insuline; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Islets of Langerhans - physiology; Keto Acids - pharmacology; Kinetics; Membrane Glycoproteins; men; messenger rna; Mice; Mice, Transgenic; N-Glycosyl Hydrolases - drug effects; N-Glycosyl Hydrolases - genetics; N-Glycosyl Hydrolases - metabolism; NAD - metabolism; NAD+ Nucleosidase - metabolism; nucleotide; nucleotides; nucleotidos; pancreas; Potassium Chloride - pharmacology; Promoter Regions, Genetic; raton; Rats; recombinant dna; Reference Values; secrecion; secretion; souris; Subcellular Fractions - enzymology; sucre du sang; Tolbutamide - pharmacology; transferencia de genes; transfert de gene; transgenic animals
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.270.50.30045

Cyclic ADP-ribose (cADPR) serves as a second messenger for Ca2+ mobilization in insulin secretion, and CD38 has both ADP-ribosyl cyclase and cADPR hydrolase activities (Takasawa, S., Tohgo, A., Noguchi, N., Koguma, T., Nata, K., Sugimoto, T., Yonekura, H., and Okamoto, H. (1993) J. Biol. Chem. 268, 26052-26054). Here, we produced transgenic mice overexpressing human CD38 in pancreatic 13 cells. The enzymatic activity of CD38 in transgenic islets was greatly increased, and ATP efficiently inhibited the cADPR hydrolase activity. The Ca2+ mobilizing activity of cell extracts from transgenic islets incubated in high glucose was 3-fold higher than that of the control, suggesting that ATP produced by glucose metabolism increased cADPR accumulation in transgenic islets. Glucose- and ketoisocaproate-induced but not tolbutamide- nor KCl-induced insulin secretions from transgenic islets were 1.7-2.3-fold higher than that of control. In glucose-tolerance tests, the transgenic serum insulin level was higher than that of control. The present study provides the first evidence that CD38 has a regulatory role in insulin secretion by glucose in 13 cells, suggesting that the Ca2+ release from intracellular cADPR-sensitive Ca2+ stores as well as the Ca2+ influx from extracellular sources play important roles in insulin secretion.