How glycogen sustains brain function: A plausible allosteric signaling pathway mediated by glucose phosphates

Abstract

Astrocytic glycogen is the sole glucose reserve of the brain. Both glycogen and glucose are necessary for basic neurophysiology and in turn for higher brain functions. In spite of low concentration, turnover and stimulation-induced degradation, any interference with normal glycogen metabolism in the brain severely affects neuronal excitability and disrupts memory formation. Here, I briefly discuss the glycogenolysis-induced glucose-sparing effect, which involves glucose phosphates as key allosteric effectors in the modulation of astrocytic and neuronal glucose uptake and phosphorylation. I further advance a novel and thus far unexplored effect of glycogenolysis that might be mediated by glucose phosphates.

Keywords: Energy metabolism; astrocytes; glucose; metabolism; neuronal-glial interaction.

Figure 1.

Schematics of the proposed glucose phosphates-mediated allosteric signaling pathway associated with astrocytic glycogenolysis. Glycogen degradation in astrocytes can be triggered by (i) adenylate kinase (AK)-mediated production of AMP after ATP hydrolysis by Na⁺/K⁺-activated adenosine triphosphatase (NKA) and/or (ii) monoamine-initiated G-protein coupled receptors (GPCRs)-mediated second-messenger signaling cascades, either the cAMP/protein kinase A (PKA) pathway or the phospholipase C (PLC)/Ca²⁺ pathway (for a detailed description, see DiNuzzo et al.). Since glycogenolysis is faster than uptake and phosphorylation of glucose, the intracellular concentration of Glc-1-P increases. Glc-1-P enhances active K⁺ uptake by NKA. Glc-1-P is isomerized by phoshoglucomutase (PGM) to Glc-6-P and also converted to Glc-1,6-P₂ by Glc-1,6-P₂ synthase (not shown). Glc-6-P inhibits glucose phosphorylation by hexokinase (HK). Besides being a cofactor in the PGM-catalyzed reaction, Glc-1,6-P₂ further inhibits HK and stimulates phosphofructokinase (PFK), thereby favoring glycolytic processing of glycogen-derived Glc-6-P and mitochondrial metabolism of downstream pyruvate (not shown) as well as oxidative phosphorylation. The decrease in substrate flow through HK entails a reduction of extracellular glucose uptake by astrocytes and glucose-sparing for neuronal utilization (dashed arrow). Overall, the effects of glycogenolysis are net changes in astrocytic uptake of potassium (increased) and glucose (decreased).