Reciprocal interaction among gasotransmitters in isolated pancreatic β-cells

We aimed to elucidate the interplay among the three well-known gas molecules, nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S), and their effects on intracellular Ca2+ concentration ([Ca2+]i) and insulin secretion in rat pancreatic β-cells. Immunofluorescence studies demonstrated the expression of constitutive enzymes that are responsible for the production of NO, CO and H2S. CO and H2S increased NO production as indicated by the increase in diaminofluorescein-2 triazole fluorescence. NO and CO induced an elevation in the sulfane sulfur pool and concomitantly H2S production. The NO- and CO-induced H2S production was partially inhibited by hypotaurine, an H2S scavenger. NO and H2S produced CO production as revealed by a myoglobin assay. A calmodulin antagonist in the absence of extracellular Ca2+ significantly attenuated NO and H2S production. NO and CO induced a [Ca2+]i increase mainly via Ca2+ release from internal stores; however, H2S induced a [Ca2+]i increase via the influx of extracellular Ca2+. NO dose-dependently stimulated basal insulin release but CO dose-dependently inhibited it. H2S showed an insignificant effect on basal insulin secretion from freshly isolated pancreatic islets. Herein, we address for the first time the reciprocal and synergistic relation among gasotransmitters with diverse effects on basal insulin secretion that regulate β-cells functions and homeostasis.