Laboratory of Neuroendocrinology - Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia; Laboratory of Cell Engineering, Celica Biomedical, Ljubljana, Slovenia.
Laboratory of Neuroendocrinology - Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Cell Calcium. 2021 May;95:102368. doi: 10.1016/j.ceca.2021.102368. Epub 2021 Feb 13.
Astroglial aerobic glycolysis, a process during which d-glucose is converted to l-lactate, a brain fuel and signal, is regulated by the plasmalemmal receptors, including adrenergic receptors (ARs) and purinergic receptors (PRs), modulating intracellular Ca and cAMP signals. However, the extent to which the two signals regulate astroglial aerobic glycolysis is poorly understood. By using agonists to stimulate intracellular α-/β-AR-mediated Ca/cAMP signals, β-AR-mediated cAMP and PR-mediated Ca signals and genetically encoded fluorescence resonance energy transfer-based glucose and lactate nanosensors in combination with real-time microscopy, we show that intracellular Ca, but not cAMP, initiates a robust increase in the concentration of intracellular free d-glucose ([glc]) and l-lactate ([lac]), both depending on extracellular d-glucose, suggesting Ca-triggered glucose uptake and aerobic glycolysis in astrocytes. When the glycogen shunt, a process of glycogen remodelling, was inhibited, the α-/β-AR-mediated increases in [glc] and [lac] were reduced by ∼65 % and ∼30 %, respectively, indicating that at least ∼30 % of the utilization of d-glucose is linked to glycogen remodelling and aerobic glycolysis. Additional activation of β-AR/cAMP signals aided to α-/β-AR-triggered [lac] increase, whereas the [glc] increase was unaltered. Taken together, an increase in intracellular Ca is the prime mechanism of augmented aerobic glycolysis in astrocytes, while cAMP has only a moderate role. The results provide novel information on the signals regulating brain metabolism and open new avenues to explore whether astroglial Ca signals are dysregulated and contribute to neuropathologies with impaired brain metabolism.
星形胶质细胞有氧糖酵解，即 d-葡萄糖转化为 l-乳酸的过程，是由质膜受体（包括肾上腺素能受体（ARs）和嘌呤能受体（PRs））调节的，调节细胞内 Ca 和 cAMP 信号。然而，两种信号调节星形胶质细胞有氧糖酵解的程度尚不清楚。通过使用激动剂刺激细胞内α-/β-AR 介导的 Ca/cAMP 信号、β-AR 介导的 cAMP 和 PR 介导的 Ca 信号以及基于遗传编码荧光共振能量转移的葡萄糖和乳酸纳米传感器结合实时显微镜，我们表明细胞内 Ca，而不是 cAMP，引发细胞内游离 d-葡萄糖 ([glc]) 和 l-乳酸 ([lac]) 浓度的剧烈增加，这两个过程都依赖于细胞外的 d-葡萄糖，表明 Ca 触发了星形胶质细胞中的葡萄糖摄取和有氧糖酵解。当糖原穿梭途径（糖原重塑过程）被抑制时，α-/β-AR 介导的 [glc] 和 [lac] 的增加分别减少了约 65%和 30%，表明至少约 30%的 d-葡萄糖利用与糖原重塑和有氧糖酵解有关。β-AR/cAMP 信号的进一步激活有助于促进 α-/β-AR 触发的 [lac] 增加，而 [glc] 的增加则没有改变。总之，细胞内 Ca 的增加是星形胶质细胞有氧糖酵解增强的主要机制，而 cAMP 只有适度的作用。该结果提供了关于调节大脑代谢的信号的新信息，并为探索星形胶质细胞 Ca 信号是否失调以及是否有助于代谢受损的神经病理学开辟了新途径。
