Arginine Thiazolidine Carboxylate Stimulates Insulin Secretion through Production of Ca2+-Mobilizing Second Messengers NAADP and cADPR in Pancreatic Islets |
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| Authors: | Dae-Ryoung Park Asif Iqbal Shawl Tae-Geun Ha Kwang-Hyun Park Seon-Young Kim Uh-Hyun Kim |
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| Institution: | 1. Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Korea.; 2. National Creative Research Laboratory for Ca2+ Signaling Network, Chonbuk National University, Jeonju, Korea.; 3. Institute of Cardiovascular Research, Chonbuk National University, Jeonju, Korea.; College of Tropical Agriculture and Human Resources, University of Hawaii, UNITED STATES, |
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| Abstract: | 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. |
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