title: Arginine Thiazolidine Carboxylate Stimulates Insulin Secretion through Production of Ca2+-Mobilizing Second Messengers NAADP and cADPR in Pancreatic Islets.
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.
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Korea; National Creative Research Laboratory for Ca2+ Signaling Network, Chonbuk National University, Jeonju, Korea.
authors.forename: Dae-Ryoung
authors.initials: DR
authors.lastname: Park
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Korea; National Creative Research Laboratory for Ca2+ Signaling Network, Chonbuk National University, Jeonju, Korea.
authors.forename: Asif Iqbal
authors.initials: AI
authors.lastname: Shawl
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Korea; National Creative Research Laboratory for Ca2+ Signaling Network, Chonbuk National University, Jeonju, Korea.
authors.forename: Tae-Geun
authors.initials: TG
authors.lastname: Ha
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Korea; National Creative Research Laboratory for Ca2+ Signaling Network, Chonbuk National University, Jeonju, Korea.
authors.forename: Kwang-Hyun
authors.initials: KH
authors.lastname: Park
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Korea; National Creative Research Laboratory for Ca2+ Signaling Network, Chonbuk National University, Jeonju, Korea.
authors.forename: Seon-Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Korea; National Creative Research Laboratory for Ca2+ Signaling Network, Chonbuk National University, Jeonju, Korea; Institute of Cardiovascular Research, Chonbuk National University, Jeonju, Korea.
authors.forename: Uh-Hyun
authors.initials: UH
authors.lastname: Kim
mesh_terms: D000818:Animals; D001120:Arginine / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D036563:Cyclic ADP-Ribose / Q000096:biosynthesis*; D000242:Cyclic AMP / Q000096:biosynthesis; D006152:Cyclic GMP / Q000378:metabolism; D015870:Gene Expression; D005978:Glutathione / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009249:NADP / Q000031:analogs & derivatives* / Q000096:biosynthesis; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D053778:Thiazolidines / Q000737:chemistry / Q000494:pharmacology*; D046509:Tissue Culture Techniques
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D011355:Prodrugs; D053778:Thiazolidines; D036563:Cyclic ADP-Ribose; D009569:Nitric Oxide; D009249:NADP; C024376:NAADP; C020213:arginine thiazolidinecarboxylate; D001120:Arginine; D000242:Cyclic AMP; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D005978:Glutathione; D006152:Cyclic GMP; D002118:Calcium