Antidiabetic effect of a prodrug of cysteine, L-2-oxothiazolidine-4-carboxylic acid, through CD38 dimerization and internalization.
CD38 is a bifunctional enzyme synthesizing (ADP-ribosyl cyclase) and degrading (cyclic ADP-ribose (cADPR) hydrolase) cADPR, a potent Ca(2+) mobilizer from intracellular pools. CD38 internalization has been proposed as a mechanism by which the ectoenzyme produced intracellular cADPR, and thiol compounds have been shown to induce the internalization of CD38. Here, we show that the disulfide bond between Cys-119 and Cys-201 in CD38 may be involved in CD38 dimerization and internalization. We tested the effect of a reducing agent, l-2-oxothiazolidine-4-carboxylic acid (OTC), a prodrug of cysteine, on CD38 internalization in pancreatic islets. OTC enhanced insulin release from isolated islets as well as CD38 internalization and cytoplasmic Ca(2+) level. Furthermore, islet cells treated with antisense CD38 oligonucleotide showed inhibition of OTC-induced insulin secretion. Intake of OTC in db/db mice ameliorated glucose tolerance, insulin secretion, and morphology of islets when compared with control mice. These data indicate that OTC improves glucose tolerance by enhancing insulin secretion via CD38/cADPR/Ca(2+) signaling machinery. Thus, OTC may represent a novel class of antidiabetic drug.
Han
Myung-Kwan
MK
Department of Biochemistry and Institute for Medical Sciences, Chonbuk National University Medical School, Chonju 561-182, Korea.
Kim
Se-Jin
SJ
Park
Young-Ran
YR
Shin
Young-Mi
YM
Park
Hyun-Jung
HJ
Park
Kum-Jae
KJ
Park
Kwang-Hyun
KH
Kim
Hyun-Kag
HK
Jang
Seon-Il
SI
An
Nyeon-Hyoung
NH
Kim
Uh-Hyun
UH
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism*; D000975:Antioxidants / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002469:Cell Separation; D003545:Cysteine / Q000737:chemistry*; D018076:DNA, Complementary / Q000378:metabolism; D019281:Dimerization; D004220:Disulfides; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009244:NAD+ Nucleosidase / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011761:Pyrrolidonecarboxylic Acid; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology*; D053778:Thiazolidines; D013997:Time Factors; D014162:Transfection
D015703:Antigens, CD; D000943:Antigens, Differentiation; D000975:Antioxidants; D001786:Blood Glucose; D018076:DNA, Complementary; D004220:Disulfides; D007004:Hypoglycemic Agents; D008164:Luminescent Proteins; D008562:Membrane Glycoproteins; D016376:Oligonucleotides, Antisense; D013844:Thiazoles; D053778:Thiazolidines; D049452:Green Fluorescent Proteins; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; C498155:Cd38 protein, mouse; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1; D005947:Glucose; D003545:Cysteine; D002118:Calcium; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid