The CD38-cyclic ADP-ribose signaling system in insulin secretion.
Glucose induces an increase in the intracellular Ca2+ concentration in pancreatic beta-cells to secrete insulin. CD38 occurs in beta-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 beta-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.
Okamoto
H
H
Department of Biochemistry, Tohoku University School of Medicine, Sendai, Miyagi, Japan.
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000246:Adenosine Diphosphate Ribose / Q000502:physiology*; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002352:Carrier Proteins; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008562:Membrane Glycoproteins; D008954:Models, Biological; D009244:NAD+ Nucleosidase / Q000502:physiology*; D010179:Pancreas / Q000378:metabolism; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D015398:Signal Transduction; D016559:Tacrolimus / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D002352:Carrier Proteins; D007328:Insulin; D008562:Membrane Glycoproteins; D019837:Ryanodine Receptor Calcium Release Channel; D000246:Adenosine Diphosphate Ribose; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D036541:ADP-ribosyl Cyclase; C498156:Cd38 protein, rat; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1; D016559:Tacrolimus