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.
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 beta 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 beta 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.
Department of Biochemistry, Tohoku University School of Medicine, Miyagi, Japan.
I
I
Kato
S
S
Takasawa
A
A
Akabane
O
O
Tanaka
H
H
Abe
T
T
Takamura
Y
Y
Suzuki
K
K
Nata
H
H
Yonekura
T
T
Yoshimoto
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D036563:Cyclic ADP-Ribose; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D007651:Keto Acids / Q000494:pharmacology; D007700:Kinetics; D008562:Membrane Glycoproteins; D051379:Mice; D008822:Mice, Transgenic; D009699:N-Glycosyl Hydrolases / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009244:NAD+ Nucleosidase / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D051381:Rats; D012016:Reference Values; D013347:Subcellular Fractions / Q000201:enzymology; D014044:Tolbutamide / Q000494:pharmacology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D007328:Insulin; D007651:Keto Acids; D008562:Membrane Glycoproteins; D009243:NAD; D036563:Cyclic ADP-Ribose; D000246:Adenosine Diphosphate Ribose; D011189:Potassium Chloride; C013082:alpha-ketoisocaproic acid; D000255:Adenosine Triphosphate; D014044:Tolbutamide; D009699:N-Glycosyl Hydrolases; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; C498155:Cd38 protein, mouse; C498156:Cd38 protein, rat; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1; D005947:Glucose