Regulation of calcium uptake/efflux from the islet-cell endoplasmic reticulum with regard to the secretion of insulin.
Figure 8 summarizes some of the processes that may impact on the secretion of insulin by regulating Ca2+ handling by the beta-cell endoplasmic reticulum. A role for calmodulin in controlling the rate of Ca2+ efflux is indicated by both the ability of the calmodulin antagonist, W7 to stimulate Ca2+ efflux and by the ability of exogenous calmodulin to antagonize Ca2+ efflux in response to inositol trisphosphate (IP3). The impact of calmodulin on this system may be to serve as link in the feedback control of cellular Ca2+. In addition to IP3, a second messenger that may link signal transduction to the release of Ca2+ is the guanine nucleotide, GTP. GTP stimulates the efflux of Ca2+ from the endoplasmic reticulum through a mechanism distinct from IP3. It will be important to determine whether extracellular glucose concentration, or other modifiers of secretion, acutely regulate the GTP concentrations in the beta-cell and to assess if this function may be altered with a decrease in beta-cell function. A variety of evidence indicates that metabolism of glucose by the beta-cell somehow plays a major role in the cellular control of insulin secretion (Hedeskov, 1980). An important link in this process may be the direct effects of glucose 6-phosphate on the handling of Ca2+ by the endoplasmic reticulum. Glucose 6-phosphate is able to increase the active uptake of Ca2+ by these membranes and also to specifically inhibit Ca2+ efflux produced by the IP3. Concentrations of glucose 6-phosphate needed to achieve these effects are likely achieved under physiological conditions (Aschroft et al., 1970). It is also easy to imagine that in diabetes when the islets are chronically exposed to high glucose that, as a result of the content of the high Km glucokinase in the islet (Meglasson and Matschinsky, 1986), higher concentrations of glucose 6-phosphate may be achieved. Under these conditions glucose 6-phosphate may contribute to the islet-cell pathology by interfering with the acute control of Ca2+ handling by the endoplasmic reticulum.
D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000502:physiology; D002463:Cell Membrane Permeability; D004072:Digitonin / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D066298:In Vitro Techniques; D007515:Islets of Langerhans / Q000378:metabolism*; D007700:Kinetics; D008954:Models, Biological
D002147:Calmodulin; D004072:Digitonin; D002118:Calcium