Ca2+ as the prime trigger of aerobic glycolysis in astrocytes. (May 2021)

• Record Type: Journal Article
• Authors: Horvat, Anemari; Muhič, Marko; Smolič, Tina; Begić, Ena; Zorec, Robert; Kreft, Marko; Vardjan, Nina
• Is Part Of: Cell calcium. Volume 95(2021)
• Publication Date: 2021-05
• Subjects: ARs adrenergic receptors -- Ca2+ calcium -- cAMP 3′, 5′-cyclic adenosine monophosphate -- [Ca2+]i intracellular concentration of Ca2+ -- [cAMP]i intracellular concentration of cAMP -- CNS central nervous system -- DAB 1, 4-dideoxy-1, 4-imino-ᴅ-arabinitol -- FLII12Pglu-700μδ6 FRET-based glucose nanosensor -- FRET fluorescence resonance energy transfer -- [glc]i cytosolic concentration of free d-glucose -- GLUT d-glucose transporter -- GP glycogen phosphorylase -- Iono ionomycin -- Iso isoprenaline -- Laconic FRET-based lactate nanosensor -- [lac]i cytosolic concentration of l-lactate -- LC locus coeruleus -- MCT monocarboxylate transporter -- NA noradrenaline -- NCX Na+/Ca2+ exchanger -- PE phenylephrine -- PRs purinergic receptors -- P2R purinergic P2 receptors, P2X, ionotropic P2 receptors -- P2Y metabotropic P2 receptors -- SOCC store-operated Ca2+ channel -- TRPC transient receptor potential canonical channel -- VGCC voltage-gated Ca2+ channel; Astrocytes -- Ca2+/cAMP signalling -- Aerobic glycolysis -- d-Glucose -- l-Lactate; Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2021.102368
• Languages: English
• ISSNs: 0143-4160

Abstract

Graphical abstract: Highlights: Ca 2+ signals are key triggers of augmented aerobic glycolysis in astrocytes. cAMP aids to Ca 2+ -driven increase in aerobic glycolysis in astrocytes. Aerobic glycolysis in astrocytes depends on extracellular d -glucose. Aerobic glycolysis in astrocytes depends on glycogen shunt activity. Abstract: 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 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 α1 -/β-AR-mediated Ca 2+ /cAMP signals, β-AR-mediated cAMP and P2 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 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 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.