Ca$^{2+}$ as the prime trigger of aerobic glycolysis in astrocytesHorvat, Anemari (Avtor) Muhič, Marko (Avtor) Smolič, Tina (Avtor) Begić, Ena (Avtor) Zorec, Robert (Avtor) Kreft, Marko (Avtor) Vardjan, Nina (Avtor) astrocytesaerobic glycolysisD-glucoseL-lactateCa$^{2+}$/cAMP signallingAstroglial 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$^{2+}$ 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$_1$-/β-AR-mediated Ca$^{2+}$/cAMP signals, β-AR-mediated cAMP and P$_2$R-mediated Ca$^{2+}$ signals and genetically encoded fluorescence resonance energy transfer-based glucose and lactate nanosensors in combination with real-time microscopy, we show that intracellular Ca$^{2+}$, 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 Ca$^{2+}$-triggered glucose uptake and aerobic glycolysis in astrocytes. When the glycogen shunt, a process of glycogen remodelling, was inhibited, the α$_1$-/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 α$_1$-/β-AR-triggered [lac]$_i$ increase, whereas the [glc]$_i$ increase was unaltered. Taken together, an increase in intracellular Ca$^{2+}$ 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$^{2+}$ signals are dysregulated and contribute to neuropathologies with impaired brain metabolism.20212022-07-20 14:24:27Članek v reviji138438UDK: 616-092ISSN pri članku: 1532-1991DOI: 10.1016/j.ceca.2021.102368COBISS_ID: 52558339sl