Effective Glucose Uptake by Human Astrocytes Requires Its Sequestration in the Endoplasmic Reticulum by Glucose-6-Phosphatase-β
| Autor: | Müller, Margit S, Fouyssac, Maxime, Taylor, Colin W |
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| Přispěvatelé: | Fouyssac, Maxime [0000-0002-9496-5836], Taylor, Colin [0000-0001-7771-1044], Apollo - University of Cambridge Repository |
| Rok vydání: | 2018 |
| Předmět: |
glucose 6-phosphate
Male Biological Transport Endoplasmic Reticulum Stress Endoplasmic Reticulum Ca(2+) signaling Article Rats Rats Sprague-Dawley astrocyte Fetus Glucose Astrocytes glucose 6-phosphatase Glucose-6-Phosphatase Animals Humans genetically encoded glucose sensor Energy Metabolism Ca2+ signaling |
| Zdroj: | Current Biology |
| DOI: | 10.17863/cam.27317 |
| Popis: | Summary After its uptake into the cytosol, intracellular glucose is phosphorylated to glucose-6-phosphate (G6P), trapping it within the cell and preparing it for metabolism. In glucose-exporting tissues, like liver, G6P is transported into the ER, where it is dephosphorylated by G6Pase-α. The glucose is then returned to the cytosol for export [1, 2]. Defects in these pathways cause glycogen storage diseases [1]. G6Pase-β, an isozyme of G6Pase-α, is widely expressed [3, 4]. Its role in cells that do not export glucose is unclear, although mutations in G6Pase-β cause severe and widespread abnormalities [5, 6, 7]. Astrocytes, the most abundant cells in the brain, provide metabolic support to neurons, facilitated by astrocytic endfeet that contact blood capillaries or neurons [8, 9, 10, 11, 12]. Perivascular endfeet are the main site of glucose uptake by astrocytes [13], but in human brain they may be several millimeters away from the perineuronal processes [14]. We show that cultured human fetal astrocytes express G6Pase-β, but not G6Pase-α. ER-targeted glucose sensors [15, 16] reveal that G6Pase-β allows the ER of human astrocytes to accumulate glucose by importing G6P from the cytosol. Glucose uptake by astrocytes, ATP production, and Ca2+ accumulation by the ER are attenuated after knockdown of G6Pase-β using lentivirus-delivered shRNA and substantially rescued by expression of G6Pase-α. We suggest that G6Pase-β activity allows effective uptake of glucose by astrocytes, and we speculate that it allows the ER to function as an intracellular “highway” delivering glucose from perivascular endfeet to the perisynaptic processes. Graphical Abstract Highlights • Glucose-6-phosphatase-β (G6Pase-β) is expressed in human astrocytes • G6P is sequestered by ER and dephosphorylated to glucose in the lumen by G6Pase-β • Loss of G6Pase-β reduces glucose uptake, intracellular ATP, and ER Ca2+ content • ER may provide a protected highway for long-range glucose transport in astrocytes Müller et al. use targeted glucose sensors to show that glucose-6-phosphate uptake by the endoplasmic reticulum of human astrocytes and its dephosphorylation in the ER by glucose-6-phosphatase-β deliver glucose to the ER lumen and sustain cellular glucose uptake. The ER lumen may provide an intracellular protected highway for glucose transport. |
| Databáze: | OpenAIRE |
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