1. Antidiabetic effect of a prodrug of cysteine, L-2-oxothiazolidine-4-carboxylic acid, through CD38 dimerization and internalization
- Author
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Kwang-Hyun Park, Hyun-Jung Park, Myung-Kwan Han, Kum-Jae Park, Young-Mi Shin, Se-Jin Kim, Seon-Il Jang, Uh-Hyun Kim, Young-Ran Park, Nyeon-Hyoung An, and Hyun-Kag Kim
- Subjects
Blood Glucose ,Time Factors ,medicine.medical_treatment ,Cell Separation ,Biochemistry ,Antioxidants ,Mice ,immune system diseases ,hemic and lymphatic diseases ,Disulfides ,Internalization ,media_common ,Mice, Inbred BALB C ,Membrane Glycoproteins ,Microscopy, Confocal ,Chemistry ,Prodrug ,Flow Cytometry ,Immunohistochemistry ,Pyrrolidonecarboxylic Acid ,medicine.anatomical_structure ,Thiazolidines ,Dimerization ,Intracellular ,Signal Transduction ,ADP-ribosyl Cyclase ,DNA, Complementary ,media_common.quotation_subject ,Green Fluorescent Proteins ,Transfection ,Cyclase ,Cell Line ,Islets of Langerhans ,NAD+ Nucleosidase ,Antigens, CD ,medicine ,Animals ,Humans ,Hypoglycemic Agents ,Cysteine ,Molecular Biology ,Dose-Response Relationship, Drug ,Pancreatic islets ,Insulin ,Cell Biology ,Oligonucleotides, Antisense ,ADP-ribosyl Cyclase 1 ,Antigens, Differentiation ,Luminescent Proteins ,Thiazoles ,Glucose ,Mutation ,Mutagenesis, Site-Directed ,Calcium ,HeLa Cells - Abstract
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.
- Published
- 2001