Monoaminergic Control of Cellular Glucose Utilization by Glycogenolysis in Neocortex and Hippocampus

Abstract

Brainstem nuclei are the principal sites of monoamine (MA) innervation to major forebrain structures. In the cortical grey matter, increased secretion of MA neuromodulators occurs in response to a wealth of environmental and homeostatic challenges, whose onset is associated with rapid, preparatory changes in neural activity as well as with increases in energy metabolism. Blood-borne glucose is the main substrate for energy production in the brain. Once entered the tissue, interstitial glucose is equally accessible to neurons and astrocytes, the two cell types accounting for most of cellular volume and energy metabolism in neocortex and hippocampus. Astrocytes also store substantial amounts of glycogen, but non-stimulated glycogen turnover is very small. The rate of cellular glucose utilization in the brain is largely determined by hexokinase, which under basal conditions is more than 90% inhibited by its product glucose-6-phosphate (Glc-6-P). During rapid increases in energy demand, glycogen is a primary candidate in modulating the intracellular level of Glc-6-P, which can occur only in astrocytes. Glycogenolysis can produce Glc-6-P at a rate higher than uptake and phosphorylation of glucose. MA neurotransmitter are released extrasinaptically by brainstem neurons projecting to neocortex and hippocampus, thus activating MA receptors located on both neuronal and astrocytic plasma membrane. Importantly, MAs are glycogenolytic agents and thus they are exquisitely suitable for regulation of astrocytic Glc-6-P concentration, upstream substrate flow through hexokinase and hence cellular glucose uptake. Conforming to such mechanism, Gerald A. Dienel and Nancy F. Cruz recently suggested that activation of noradrenergic locus coeruleus might reversibly block astrocytic glucose uptake by stimulating glycogenolysis in these cells, thereby anticipating the rise in glucose need by active neurons. In this paper, we further develop the idea that the whole monoaminergic system modulates both function and metabolism of forebrain regions in a manner mediated by glycogen mobilization in astrocytes.

Aerobic glycolysis during brain activation: adrenergic regulation and influence of norepinephrine on astrocytic metabolism

“…A novel, alternative explanation for the rise in extracellular glucose level during brain activation comes from DiNuzzo et al . (). They propose that glycogen mobilization by monoamines increases glucose‐6‐P level, thereby augmenting its feedback inhibition of hexokinase, reducing astrocytic glucose metabolism, and facilitating blood‐borne glucose availability for neurons.…”

Metabolic Dysregulation Contributes to the Progression of Alzheimer’s Disease

“…F6P, which continues to participate in the subsequent steps of glycolysis, is converted into pyruvate. On the other hand, G6P not only participates in both glycogen synthesis and the PPP, but also non-competitively inhibits hexokinase (DiNuzzo et al, 2015). Phosphofructokinase (PFK), which takes part in the second step of glycolysis, catalyzes F6P into fructose 1,6-bisphosphate (F1,6BP).…”

Role of Glycogenolysis in Memory and Learning: Regulation by Noradrenaline, Serotonin and ATP

“…Our data clearly show that glycogen has an active role in astrocytic function. This may in turn also influence neuronal metabolism because glycogenolysis may inhibit astrocytic glucose consumption and thereby make more glucose available for neurons ( DiNuzzo et al, 2012 , 2015 ). Since glycogen turnover is slow under resting conditions, the question arises as to how fast it can be recruited in cells and are there readily accessible stores with fast turnover in brain regions important for memory.…”