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Arginine thiazolidine carboxylate stimulates insulin secretion through production of Ca2+-mobilizing second messengers NAADP and cADPR in pancreatic islets
- Arginine thiazolidine carboxylate stimulates insulin secretion through production of Ca2+-mobilizing second messengers NAADP and cADPR in pancreatic islets
- Park, Dae Ryoung; Shawl, Asif Iqbal; Ha, Tae Geun; Park, Kwang Hyun; Kim, Seon Young; Kim, Uh Hyun
- Issue Date
- PLoS ONE, 10(8)
- Article Type
- Animal Cell; Animal Experiment; Antidiabetic Activity; Arginine; Arginine Thiazolidine Carboxylic Acid; Calcium Cell Level; Calcium Signaling; CD38 Antigen; Concentration Response; Controlled Study; Cyclic Adenosine Diphosphate Ribose; Dose-Response; Drug Potency; Enzyme Linked Immunosorbent Assay; Glitazone Derivative; Glucose; Glucose Blood Level; Glutathione; Insulin Release; Male; Nicotinic Acid Adenine Dinucleotide Phosphate; Nitric Oxide; Nitric Oxide Synthase; Non-Human; Pancreas Islet Beta Cell; Protein Function; Protein Synthesis; Rat; Unclassified Drug
- Oxothiazolidine carboxylic acid is a prodrug of cysteine that acts as an anti-diabetic agent via insulin secretion and the formation of the Ca2+-mobilizing second messenger, cyclic ADP-ribose (cADPR). Here we show that a hybrid compound, arginine thiazolidine carboxylate (ATC), increases cytoplasmic Ca2+ in pancreatic β-cells, and that the ATC-induced Ca2+ signals result from the sequential formation of two Ca2+-mobilizing second messengers: nicotinic acid adenine dinucleotide phosphate (NAADP) and cADPR. Our data demonstrate that ATC has potent insulin-releasing properties, due to the additive action of its two components; thiazolidine carboxylate (TC) and L-arginine. TC increases glutathione (GSH) levels, resulting in cAMP production, followed by a cascade pathway of NAADP/nitric oxide (NO)/cGMP/cADPR synthesis. L-arginine serves as the substrate for NO synthase (NOS), which results in cADPR synthesis via cGMP formation. Neuronal NOS is specifically activated in pancreatic β-cells upon ATC treatment. These results suggest that ATC is an ideal candidate as an anti-diabetic, capable of modulating the physiological Ca2+ signalling pathway to stimulate insulin secretion. © 2015 Park et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
- Public Library of Science
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