Critical Roles of Carbon Monoxide and Nitric Oxide in Ca2+ Signaling for Insulin Secretion in Pancreatic Islets
Abstract
Glucagon-like peptide-1 (GLP-1) increases intracellular Ca2+ concentrations, resulting in insulin secretion from pancreatic β-cells through the sequential production of Ca2+ mobilizing messengers nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-ribose (cADPR). We previously found that NAADP activates the neuronal type of nitric oxide (NO) synthase (nNOS), the product of which, NO, activates guanylyl cyclase to produce cyclic guanosine monophosphate (cGMP), which, in turn, induces cADPR formation. Our aim was to explore the relationship between Ca2+ signals and gasotransmitters formation in insulin secretion in β-cells upon GLP-1 stimulation. We show that NAADP-induced cGMP production by nNOS activation is dependent on carbon monoxide (CO) formation by heme oxygenase-2 (HO-2). Treatment with exogenous NO and CO amplifies cGMP formation, Ca2+ signal strength, and insulin secretion, whereas this signal is impeded when exposed to combined treatment with NO and CO. Furthermore, CO potentiates cGMP formation in a dose-dependent manner, but higher doses of CO inhibited cGMP formation. Our data with regard to zinc protoporphyrin, a HO inhibitor, and HO-2 knockdown, revealed that NO-induced cADPR formation and insuli...Continue Reading
References
Evaluation of islet heme oxygenase-CO and nitric oxide synthase-NO pathways during acute endotoxemia
Carbon monoxide stimulates insulin release and propagates Ca2+ signals between pancreatic beta-cells
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