Glucose metabolism in nerve terminals

Abstract

Nerve terminals in the brain carry out the primary form of intercellular communication between neurons. Neurotransmission, however, requires adequate supply of ATP to support energetically demanding steps, including the maintenance of ionic gradients, reversing changes in intracellular Ca²⁺ that arise from opening voltage-gated Ca²⁺ channels, as well recycling synaptic vesicles. The energy demands of the brain are primarily met by glucose which is oxidized through glycolysis and oxidative phosphorylation to produce ATP. The pathways of ATP production have to respond rapidly to changes in energy demand at the synapse to sustain neuronal activity. In this review, we discuss recent progress in understanding the mechanisms regulating glycolysis at nerve terminals, their contribution to synaptic function, and how dysregulation of glycolysis may contribute to neurodegeneration.

Figure 1. Glut4 vesicles rapidly insert into the presynaptic plasma membrane in response to neuronal firing

(A) Schematic drawing of the use of Glut4 tagged with pHluorin (pH) to visualize its trafficking in neurons. pHluorin is pH sensitive and its fluorescence is quenched in the acidic environment of endosomes but not when exposed to extracellular space. (B) Glut4-pH fluorescence (pseudocolor) increases in presynaptic boutons (arrowhead) after electrical stimulation with 600 action potentials (APs). (C) Average trace of Glut4-pH in response to stimulation. (Adapted from[20]). Gray lines are standard errors. Scale bar, 5μm.

Figure 2. Neuronal activity stimulates glycolysis in presynaptic boutons

(A) Presynaptic APs drive the translocation of the glucose transporter Glut4 to the membrane where it increases glucose uptake. (B) Activity also stimulates the formation of a cluster of glycolytic enzymes (metabolon) that can rapidly metabolize glucose. (C) Glycolysis results in the production of pyruvate, a substrate for mitochondrial OxPhos, (D) which together with glycolysis produces ATP (E) to power the recycling of SVs following their release during synaptic activity.

Figure 3. The central role of NAD⁺ shuttle systems in glucose metabolism

(A) The malate-aspartate (MA) shuttle uses cytoplasmic and mitochondrial malate dehydrogenases to convert aspartate to malate and NADH to NAD⁺ in the cytosol, as well as the reverse in the mitochondrial matrix. Malate and aspartate are exchanged between the two compartments by the malate/α-ketoglutarate and the aspartate/glutamate antiporters. (B) In the glycerol-3-phosphate shuttle, cytosolic glycerol-3-phosphate dehydrogenase converts NADH to NAD⁺ and dihydroxyacetone phosphate to glycerol-3-phosphate while the mitochondrial enzyme reverses the reaction releasing electrons to the electron transport chain. The cytosolic NAD⁺ produced by the shuttles serves as cofactor driving glycolysis, while (C) mitochondrial NADH produced by the shuttles and the TCA cycle drives the formation of a proton gradient by the electron transport chain (D) which is then used by the F₁F₀-ATPase to synthesize ATP. Asp: aspartate; Glu: glutamate; cMDH, mMDH: cytoplasmic and mitochondrial malate dehydrogenase; α-KG: α-ketoglutarate; G3P: glycerol-3-phosphate; DHAP: dihydroxyacetone phosphate; cGPDH and mGPDH: cytoplasmic and mitochondrial glycerol-3-phosphate dehydrogenase; ETC: electron transport chain. TCA cycle: tricarboxylic cycle.