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.

CD38-cADPR-SERCA Signaling Axis Determines Skeletal Muscle Contractile Force in Response to β-Adrenergic Stimulation

“…CD38 has been well characterized as a mammalian prototype of ADP-ribosyl cyclase (ARC), which can produce two Ca 2+ mobilizing messengers: cADPR and NAADP [12, 13]. However, there also exist as-yet-unidentified non-CD38 ARCs and NAADP-synthesizing enzymes in mammalian tissues, including the skeletal muscle [10, 14, 15]. cADPR is known to mobilize Ca 2+ from the SR Ca 2+ stores through the activation of ryanodine receptors (RyRs) in a wide range of cell types [16, 17].…”

Atypical KCNQ1/Kv7 channel function in a neonatal diabetes patient: Hypersecretion preceded the failure of pancreatic β-cells

“…Considering that intracellular Ca 2+ can modulate GSIS in β-cells, 49 , 50 we wondered whether insulin secretion could be still stimulated from an intracellular depot at day 40. To this end, we treated day 40 SC-islets with arginine (Arg), which is known to increase Ca 2+ release from the endoplasmic reticulum (ER) and depolarize β-cells.…”

Molecular Mechanisms of the Melatonin Receptor Pathway Linking Circadian Rhythm to Type 2 Diabetes Mellitus

“…cADPR then mediates Ca 2+ release from the ER, a process called store-operated Ca 2+ entry (SOCE). Ca 2+ continues to induce transmembrane Ca 2+ channel opening, resulting in Ca 2+ influx and resultant insulin secretion [ 30 ]. Noticeably, melatonin-bound MT 2 was found to exert an additional negative effect on the synthesis of NO [ 31 ], suggesting that the MT 2 pathway exerts an additional inhibitory impact on insulin synthesis.…”