Ca 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 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.