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. 2012 Mar 2;4:3.
doi: 10.3389/fnene.2012.00003. eCollection 2012.

Brain Glycogen-New Perspectives on Its Metabolic Function and Regulation at the Subcellular Level

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Free PMC article

Brain Glycogen-New Perspectives on Its Metabolic Function and Regulation at the Subcellular Level

Linea F Obel et al. Front Neuroenergetics. .
Free PMC article

Abstract

Glycogen is a complex glucose polymer found in a variety of tissues, including brain, where it is localized primarily in astrocytes. The small quantity found in brain compared to e.g., liver has led to the understanding that brain glycogen is merely used during hypoglycemia or ischemia. In this review evidence is brought forward highlighting what has been an emerging understanding in brain energy metabolism: that glycogen is more than just a convenient way to store energy for use in emergencies-it is a highly dynamic molecule with versatile implications in brain function, i.e., synaptic activity and memory formation. In line with the great spatiotemporal complexity of the brain and thereof derived focus on the basis for ensuring the availability of the right amount of energy at the right time and place, we here encourage a closer look into the molecular and subcellular mechanisms underlying glycogen metabolism. Based on (1) the compartmentation of the interconnected second messenger pathways controlling glycogen metabolism (calcium and cAMP), (2) alterations in the subcellular location of glycogen-associated enzymes and proteins induced by the metabolic status and (3) a sequential component in the intermolecular mechanisms of glycogen metabolism, we suggest that glycogen metabolism in astrocytes is compartmentalized at the subcellular level. As a consequence, the meaning and importance of conventional terms used to describe glycogen metabolism (e.g., turnover) is challenged. Overall, this review represents an overview of contemporary knowledge about brain glycogen and its metabolism and function. However, it also has a sharp focus on what we do not know, which is perhaps even more important for the future quest of uncovering the roles of glycogen in brain physiology and pathology.

Keywords: astrocyte; glutamate; glycogen phosphorylase; glycogen shunt; glycogen synthase; microdomain; neuron; noradrenaline.

Figures

Figure 1
Figure 1
Regulation of glycogen metabolism. The cAMP level is increased by adenylate cyclase and decreased by phosphodiesterase. Depending on the isoforms of these two enzymes, calcium can be either inhibiting or activating. An increased cAMP level leads to activation of protein kinase A, which in turn activates phosphorylase kinase. Phosphorylation by phosphorylase kinase, which requires calcium for activation, stimulates glycogen phosphorylase. Glycogen phosphorylase is also allosterically inhibited by ATP and activated by AMP, which accumulates during ATP depletion. Glycogen synthase is deactivated through phosphorylation by protein kinase A, phosphorylase kinase and glycogen synthase kinase 3. Glycogen synthase is activated by protein phosphatase 1, which inhibits phosphorylase kinase and glycogen phosphorylase. Glucose entering the cell is phosphorylated by hexokinase to glucose-6-phosphate and subsequently enters either glycolysis or the glycogen shunt, the latter constituting metabolism of glucose via glycogen. In glycogenesis one ATP equivalent in form of UTP is used by UDP-glucose pyrophosphorylase. Thus, glycogenolysis and subsequent glycolysis of glucose-6-phosphate entail a net gain of two ATP, whereas glycolysis of glucose-6-phosphate derived directly from glucose produces three ATP.
Figure 2
Figure 2
Regulatory differences of GP isoforms as a possible explanation for Lafora body distribution. An increased AMP concentration leads to activation of AMP-activated protein kinase, which activates the laforin-malin complex, causing degradation of protein targeting glycogen. Since protein targeting glycogen is needed to activate protein phosphatase 1, which in turn would activate glycogen synthase and inhibit glycogen phosphorylase, this would lead to degradation of glycogen by glycogen phosphorylase. In addition, glycogen phosphorylase is allosterically activated by an increased AMP level, further shifting the balance in favor of glycogen breakdown. The main astrocytic isoform of glycogen phosphorylase (brain-GP) is activated mostly allosterically and less by phosphorylation, in contrast to the muscle isoform (muscle-GP). This regulatory difference could explain why lack of laforin/malin activity in Lafora disease leads to formation of Lafora bodies in muscle and other tissues, but not in astrocytes.
Figure 3
Figure 3
Glucose but not lactate supports synaptic activity. Cultured (glutamatergic) cerebellar neurons increase the utilization of glucose but not lactate during synaptic activity as evidenced by increased labeling in glutamate (expressed as percent molecular carbon labeling, MCL; see below) from 13C-labeled glucose but not 13C-labeled lactate when subjected to pulses of the glutamate receptor agonist NMDA (data from Bak et al., 2006). Pulses of NMDA induce depolarization and pulsatile release of neurotransmitter glutamate in these cultures (Bak et al., 2003). Thus, cultured neurons rely on oxidative metabolism of glucose but not lactate when engaged in neurotransmission activity. The experiments were performed by superfusing the cultured cerebellar neurons in the presence of either [U-13C]glucose (2.5 mM; Glc in bold letters) and lactate (1 mM) or [U-13C]lactate (1 mM; Lac in bold letters) and glucose (2.5 mM) and repetitive depolarization (black bars) was induced by pulses of NMDA (300 μ M) plus potassium (15 mM). The data represents the molecular carbon labeling (MCL) in percent (see Bak et al., for a definition of MCL) of glutamate ± SD MCL (%) is a measure of labeling in the entire glutamate pool, e.g., a MCL of 20% means that 20% of all carbon atoms in the glutamate pool are 13C. Thus, an increase in MCL of glutamate means that the labeled substrate was metabolized to pyruvate and further oxidized in the TCA cycle to a higher extent. Glucose is metabolized to pyruvate via glycolysis and lactate via the lactate dehydrogenase-catalyzed reaction. Glutamate reflects the labeling in the TCA cycle intermediates, since glutamate is labeled via its cognate keto acid α-ketoglutarate, an intermediate in the TCA cycle. For a thorough discussion of this, please see Bak et al. (2006). Statistically significant differences between the control (gray bars) and those that were repetitively depolarized are indicated by asterisks and determined using an unpaired, two-tailed Student's t-test. *P < 0.05.
Figure 4
Figure 4
Glucose but not lactate supports neurotransmitter homeostasis. The ability of cultured (glutamatergic) cerebellar neurons to perform re-uptake of release D-[3H]aspartate (pre-loaded marker of glutamate release) during superfusion is diminished in the presence of lactate as compared to the presence of glucose (data from Bak et al., 2006). This is evidenced by an increase in the apparent pulsatile NMDA-induced release of D-[3H]aspartate in the presence of lactate; however, since this increase was abolished by the additional presence of the glutamate transport blocker TBOA, it most likely reflects a diminished ability to take up a fraction of the released D-[3H]aspartate. Experimentally, cultured cerebellar neurons were superfused and the depolarization-coupled release of preloaded D-[3H]aspartate evoked by 30 s pulses of NMDA (300 μ M) plus potassium (15 mM) was quantified (see Bak et al., for details). The effect of TBOA (100 μ M) on the release in the presence of glucose (2.5 mM, black and open bars) or lactate (1 mM, hatched and gray bars) was investigated. The release in the presence of glucose alone was used as a reference and normalized to 100 (black bar). The results are averages ± SD. Statistically significant differences were calculated using One-Way ANOVA followed by a Tukey–Kramer post hoc test. *Significantly different from the other three conditions (P < 0.01).
Figure 5
Figure 5
2-Deoxy-[3H]glucose transport and metabolism is accelerated in cultured astrocytes exposed to norepinephrine. Astrocyte cultures were superfused with medium containing 2.5 mM of glucose in the absence (control; white bars) or presence of 100 μ M norepinephrine (NE; blacks bar). The cultures were superfused for 15, 30, 45, or 60 min (n = 3–4) and during the last 15 min tracer amounts of 2-deoxy-[3H]glucose (2DG) were added to the superfusion medium. The astrocytes were extracted with ethanol and the extent of 2DG uptake was determined by measuring radioactivity in cell extracts (counts per minute; CPM). The 2DG uptake reflects both glucose transport and subsequent metabolism. The presence of NE gave rise to an increase in 2DG uptake in all time periods compared to controls. No significant differences were observed between time periods within controls. However, in astrocytes exposed to NE, the 2DG uptake was significantly higher from 30 to 45 min compared to all other time periods during NE exposed conditions. * and # indicate statistically significant differences between control and NE exposed astrocytes, and amongst NE exposed astrocytes, respectively (One-Way ANOVA followed by Bonferroni post hoc test, P < 0.05).
Figure 6
Figure 6
Glycolysis and TCA cycle metabolism are augmented in cultured astrocytes exposed to norepinephrine. Cultured astrocytes were superfused for 60 min with medium containing 2.5 mM of [1,6-13C]glucose in the absence (control; white bars) or presence of 100 μ M norepinephrine (NE; black bars). The percent 13C enrichment in lactate, reflecting glycolytic activity (A) and glutamate, reflecting TCA cycle metabolism of acetyl-coA derived from glucose (B) was monitored employing liquid chromatography—mass spectrometric (LC-MS) analyses. Statistically significant differences between controls and NE treated astrocytes were determined using an unpaired Student's T-test (P < 0.05) and are indicated by an asterisk (*). Data modified from Walls et al. (2009).

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