Ca 2+ 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 β-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 β-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 β-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.