title: Ca2+ microdomains and the control of insulin secretion.
abstract: Nutrient-induced increases in intracellular free Ca(2+) concentrations are the key trigger for insulin release from pancreatic islet beta-cells. These Ca(2+) changes are tightly regulated temporally, occurring as Ca(2+) influx-dependent baseline oscillations. We explore here the concept that locally high [Ca(2+)] concentrations (i.e. Ca(2+) microdomains) may control exocytosis via the recruitment of key effector proteins to sites of exocytosis. Importantly, recent advances in the development of organelle- and membrane-targeted green fluorescent protein (GFP-) or aequorin-based Ca(2+) indicators, as well as in rapid imaging techniques, are providing new insights into the potential role of these Ca(2+) microdomains in beta-cells. We summarise here some of the evidence indicating that Ca(2+) microdomains beneath the plasma membrane and at the surface of large dense core vesicles may be important in the normal regulation of insulin secretion, and may conceivably contribute to "ATP-sensitive K(+)-channel independent" effects of glucose. We also discuss evidence that, in contrast to certain non-excitable cells, direct transfer of Ca(2+) from the ER to mitochondria via localised physical contacts between these organelles is relatively less important for efficient mitochondrial Ca(2+) uptake in beta-cells. Finally, we discuss evidence from single cell imaging that increases in cytosolic Ca(2+) are not required for the upstroke of oscillations in mitochondrial redox state, but may underlie the reoxidation process.
authors.affiliation: Department of Cell Biology, Division of Medicine, Imperial College London, Sir Alexander Fleming Building, London, UK. g.a.rutter@bristol.ac.uk
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsuboi
authors.forename: Magalie A
authors.initials: MA
authors.lastname: Ravier
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology*; D002462:Cell Membrane / Q000502:physiology / Q000648:ultrastructure; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005089:Exocytosis / Q000502:physiology; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology*; D021962:Membrane Microdomains / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D051938:Munc18 Proteins / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D022142:Secretory Vesicles / Q000502:physiology / Q000648:ultrastructure
chemical_list: D007328:Insulin; D051938:Munc18 Proteins; D011493:Protein Kinase C; D005947:Glucose; D002118:Calcium