Glutamate Metabolism in the Brain Focusing on Astrocytes

Abstract

Metabolism of glutamate, the main excitatory neurotransmitter and precursor of GABA, is exceedingly complex and highly compartmentalized in brain. Maintenance of these neurotransmitter pools is strictly dependent on the de novo synthesis of glutamine in astrocytes which requires both the anaplerotic enzyme pyruvate carboxylase and glutamine synthetase. Glutamate is formed directly from glutamine by deamidation via phosphate activated glutaminase a reaction that also yields ammonia. Glutamate plays key roles linking carbohydrate and amino acid metabolism via the tricarboxylic acid (TCA) cycle, as well as in nitrogen trafficking and ammonia homeostasis in brain. The anatomical specialization of astrocytic endfeet enables these cells to rapidly and efficiently remove neurotransmitters from the synaptic cleft to maintain homeostasis, and to provide glutamine to replenish neurotransmitter pools in both glutamatergic and GABAergic neurons. Since the glutamate-glutamine cycle is an open cycle that actively interfaces with other pathways, the de novo synthesis of glutamine in astrocytes helps to maintain the operation of this cycle. The fine-tuned biochemical specialization of astrocytes allows these cells to respond to subtle changes in neurotransmission by dynamically adjusting their anaplerotic and glycolytic activities, and adjusting the amount of glutamate oxidized for energy relative to direct formation of glutamine, to meet the demands for maintaining neurotransmission. This chapter summarizes the evidence that astrocytes are essential and dynamic partners in both glutamatergic and GABAergic neurotransmission in brain.

AMPK Activation Affects Glutamate Metabolism in Astrocytes

“…NO also induced inhibition of mitochondrial respiration, but that effect was not shown to be linked to the activation of AMPK [32]. In the brain, astrocytes surround synapses and take up and metabolize glutamate as energy substrate, in addition to glucose [2]. In the presence of glutamate, activation of AMPK had no significant effect on glucose uptake in astrocytes.…”

“…This suggests that the essential parts of the glutamate-glutamine cycle, i.e. glutamate uptake, glutamine synthesis and release are not affected by AMPK activation, although glutamate transport and synthesis of glutamine are energy requiring processes (see Schousboe et al [2] ). In contrast, the entrance of glutamate into the TCA cycle was decreased as observed by a reduced a-ketoglutarate (M ?…”

“…As an alternative to conversion to glutamine, glutamate taken up by astrocytes may enter oxidative metabolism in the TCA cycle via a-ketoglutarate. a-Ketoglutarate can be formed from glutamate by transamination catalyzed primarily by aspartate aminotransferase (AAT), or by oxidative deamination via the action of glutamate dehydrogenase (GDH) [2,3]. The oxidative deamination leads to an elevation of the total amount of TCA cycle intermediates, which catalytically facilitates glucose oxidation.…”

“…Glutamate is released from glutamatergic neurons and interacts with receptors at the post-synaptic terminal of the receiving neuron. Astrocytes surrounding the synapses are essential in order to terminate neurotransmission since the majority of glutamate is taken up and metabolized by astrocytes [2]. Glutamate is an important substrate to support energy metabolism in astrocytes either via complete oxidative degradation or by providing a net synthesis of tricarboxylic acid (TCA) cycle intermediates that increases the capacity for glucose oxidation [3,4].…”

p97/VCP promotes degradation of CRBN substrate glutamine synthetase and neosubstrates

“…In the brain, GS is highly expressed in astrocytes and plays a critical role in regulating the glutamine-glutamate cycle between astrocytes and neurons (56). In astrocytes, GS combines glutamate and ammonia to form glutamine, which then is transferred to neurons and converted to glutamate by mitochondrial glutaminase (57).…”