NAADP:: A new second messenger for glucose-induced Ca2+ responses in clonal pancreatic β cells

Important questions remain concerning how elevated blood glucose levels are coupled to insulin secretion from pancreatic beta cells and how this process is impaired in type 2 diabetes [1]. Glucose uptake and metabolism in beta cells cause the intracellular Ca2+ concentration ([Ca2+](i)) to increase to a degree necessary and sufficient for triggering insulin release [2]. Although both Ca2+ influx and Ca2+ release from internal stores are critical [3, 4], the roles of inositol 1,4,5-trisphosphate (IP3) and cyclic adenosine dinucleotide phosphate ribose (cADPR) in regulating the latter have proven equivocal [5, 6]. Here we show that glucose also increases [Ca2+](i) via the novel Ca2+-mobilizing agent nicotinic acid adenine dinucleotide phosphate (NAADP) in the insulin-secreting beta-cell line MIN6. NAADP binds to specific, high-affinity membrane binding sites and at low concentrations elicits robust Ca2+ responses in intact cells. Higher concentrations of NAADP inactivate NAADP receptors and attenuate the glucose-induced Ca2+ increases. Importantly, glucose stimulation increases endogenous NAADP levels, providing strong evidence for recruitment of this pathway. In conclusion, our results support a model in which NAADP mediates glucose-induced Ca2+ signaling in pancreatic beta cells and are the first demonstration in mammalian cells of the presence of endogenous NAADP levels that can be regulated by a physiological stimulus.