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 alpha(1)-/beta-AR-mediated Ca2+/ cAMP signals, beta-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 Dglucose ([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 alpha(1)-/beta-AR-mediated increases in [glc] i and [lac] i were reduced by similar to 65 % and similar to 30 %, respectively, indicating that at least similar to 30 % of the utilization of D-glucose is linked to glycogen remodelling and aerobic glycolysis. Additional activation of beta-AR/cAMP signals aided to alpha(1)-/beta-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.

Automated summary

The study demonstrates that intracellular Ca2+ plays a significant role in regulating astrocytic aerobic glycolysis, while cAMP has a minor impact. Approximately 30% of D-glucose utilization is linked to glycogen remodeling and aerobic glycolysis. These findings provide new insights into the signals regulating brain metabolism.