Ca2+ as the prime trigger of aerobic glycolysis in astrocytes.
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 Ca2+ and cAMP signals. However, the extent to which the two signals regulate astroglial aerobic glycolysis is poorly understood. By using agonists to stimulate intracellular α1-/β-AR-mediated Ca2+/cAMP signals, β-AR-mediated cAMP and P2R-mediated Ca2+ signals and genetically encoded fluorescence resonance energy transfer-based glucose and lactate nanosensors in combination with real-time microscopy, we show that intracellular Ca2+, but not cAMP, initiates a robust increase in the concentration of intracellular free d-glucose ([glc]i) and l-lactate ([lac]i), both depending on extracellular d-glucose, suggesting Ca2+-triggered glucose uptake and aerobic glycolysis in astrocytes. When the glycogen shunt, a process of glycogen remodelling, was inhibited, the α1-/β-AR-mediated increases in [glc]i and [lac]i 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 α1-/β-AR-triggered [lac]i increase, whereas the [glc]i increase was unaltered. Taken together, an increase in intracellular Ca2+ 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 Ca2+ signals are dysregulated and contribute to neuropathologies with impaired brain metabolism.
['Horvat|Anemari|A|', 'Muhič|Marko|M|', 'Smolič|Tina|T|', 'Begić|Ena|E|', 'Zorec|Robert|R|', 'Kreft|Marko|M|', 'Vardjan|Nina|N|']
Aerobic glycolysis Astrocytes d-Glucose l-Lactate Ca(2+)/cAMP signalling