title: NAADP: a new second messenger for glucose-induced Ca2+ responses in clonal pancreatic beta cells.
abstract: 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. Glucose uptake and metabolism in beta cells cause the intracellular Ca(2+) concentration ([Ca(2+)](i)) to increase to a degree necessary and sufficient for triggering insulin release. Although both Ca(2+) influx and Ca(2+) release from internal stores are critical, the roles of inositol 1,4,5-trisphosphate (IP(3)) and cyclic adenosine dinucleotide phosphate ribose (cADPR) in regulating the latter have proven equivocal. Here we show that glucose also increases [Ca(2+)](i) via the novel Ca(2+)-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 Ca(2+) responses in intact cells. Higher concentrations of NAADP inactivate NAADP receptors and attenuate the glucose-induced Ca(2+) 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 Ca(2+) 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.
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom. roser.masgrau-juanola@pharm.ox.ac.uk
authors.forename: Roser
authors.initials: R
authors.lastname: Masgrau
authors.forename: Grant C
authors.initials: GC
authors.lastname: Churchill
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Morgan
authors.forename: Stephen J H
authors.initials: SJ
authors.lastname: Ashcroft
authors.forename: Antony
authors.initials: A
authors.lastname: Galione
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D009249:NADP / Q000031:analogs & derivatives* / Q000378:metabolism*; D011869:Radioligand Assay; D015290:Second Messenger Systems / Q000502:physiology*
chemical_list: D007328:Insulin; D009249:NADP; C024376:NAADP; D005947:Glucose; D002118:Calcium