Astrocytic glycogenolysis: mechanisms and functions

Abstract

Until the demonstration little more than 20 years ago that glycogenolysis occurs during normal whisker stimulation glycogenolysis was regarded as a relatively uninteresting emergency procedure. Since then, a series of important astrocytic functions has been shown to be critically dependent on glycogenolytic activity to support the signaling mechanisms necessary for these functions to operate. This applies to glutamate formation and uptake and to release of ATP as a transmitter, stimulated by other transmitters or elevated K(+) concentrations and affecting not only other astrocytes but also most other brain cells. It is also relevant for astrocytic K(+) uptake both during the period when the extracellular K(+) concentration is still elevated after neuronal excitation, and capable of stimulating glycogenolytic activity, and during the subsequent undershoot after intense neuronal activity, when glycogenolysis may be stimulated by noradrenaline. Both elevated K(+) concentrations and several transmitters, including the β-adrenergic agonist isoproterenol and vasopressin increase free cytosolic Ca(2+) concentration in astrocytes, which stimulates phosphorylase kinase so that it activates the transformation of the inactive glycogen phosphorylase a to the active phosphorylase b. Contrary to common belief cyclic AMP plays at most a facilitatory role, and only when free cytosolic Ca(2+) concentration is also increased. Cyclic AMP is not increased during activation of glycogenolysis by either elevated K(+) concentrations or the stimulation of the serotonergic 5-HT(2B) receptor. Not all agents that stimulate glycogenolysis do so by directly activating phophorylase kinase--some do so by activating processes requiring glycogenolysis, e.g. for synthesis of glutamate.

The metabolic trinity, glucose–glycogen–lactate, links astrocytes and neurons in brain energetics, signaling, memory, and gene expression

“…Recent studies extend the notion that glycogen is not only a dynamic component of brain energetics during activation, it is also selectively used in the presence of glucose to support memory consolidation [23,34,48,64], neuronal signaling in the locus coeruleus [65], and specific astrocyte functions, such as K + and glutamate uptake, calcium homeostasis, and other activities [33,46,51]. Neuronal protection by glycogen-derived lactate during severe hypoglycemia or aglycemia is important for patients, but not relevant to normal brain that is never deprived of glucose.…”

“…Because the locus coeruleus is the primary source of noradrenaline in the brain, ␤-receptor blockade implicates this neurotransmitter system in control of glucose uptake and utilization, glycogenolysis, and, perhaps, oxygen consumption during activation and exercise. Astrocytes are known targets of the locus coeruleus, and they have ␣ 1 -, ␣ 2 -, ␤ 1 -and ␤ 2 -adrenergic receptors linked to different second messenger and signaling pathways that modulate their glucose transport, glycolysis, oxidative metabolism, glycogen synthesis and degradation, glutamate uptake, glutamine hydrolysis, and other activities; in general, these processes are stimulated in cultured astrocytes by receptor agonists, with the specific effects dependent on receptor subtypes and signaling pathways [29,32,33,50,51]. Noradrenergic pathway intervention can cause either a rise or fall in brain glucose utilization in animals, depending on condition (with or without stimulation), brain region, and the agonists or antagonists used to target adrenoceptor subtypes [36,38,40,59,60].…”

Brain Glycogen Decreases During Intense Exercise Without Hypoglycemia: The Possible Involvement of Serotonin

“…It has also been recently reported that glycogenolysis during brain activation is necessary for astrocytes for K ? homeostasis in the brain [35][36][37]. This research has indicated the new role of astrocytic glycogenolysis in activations of astrocytes themselves.…”

Technical and experimental features of Magnetic Resonance Spectroscopy of brain glycogen metabolism

“…For example, glycogen has been proposed as an expeditious energy source supporting glutamatergic neurotransmission [31]. In agreement, brain glycogen was shown to be of particular relevance during brain activation [32,33] and learning [34e36], when increasing energy demands need to be rapidly met. Conversely, cerebral glycogen stores have to be adequately replenished when neuronal activity is low and a glucose surplus is available, what has been shown to occur during anesthesia, sleeping or hibernation [16].…”