The dual face of glutamate: from a neurotoxin to a potential survival factor—metabolic implications in health and disease

Abstract

Glutamate is the major excitatory neurotransmitter in the central nervous system. Beyond this function, glutamate also plays a key role in intermediary metabolism in all organs and tissues, linking carbohydrate and amino acid metabolism via the tricarboxylic acid cycle. Under both physiological and pathological conditions, we have recently found that the ability of glutamate to fuel cell metabolism selectively relies on the activity of two main transporters: the sodium-calcium exchanger (NCX) and the sodium-dependent excitatory amino-acid transporters (EAATs). In ischemic settings, when glutamate is administered at the onset of the reoxygenation phase, the coordinate activity of EAAT and NCX allows glutamate to improve cell viability by stimulating ATP production. So far, this phenomenon has been observed in both cardiac and neuronal models. In this review, we focus on the most recent findings exploring the unusual activity of glutamate as a potential survival factor in different settings. KeywordsAmino-acid transporters • ATP • Cell viability • Ischemia/reperfusion • Sodium-calcium exchanger Abbreviations AD Alzheimer's disease ALS Amyotrophic lateral sclerosis AGCs Aspartate/glutamate carriers AMPA α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid DL-TBOA DL-Threo-β-benzyloxyaspartic acid EAAC1 Excitatory amino acid carrier 1 EAATs Excitatory amino-acid transporters KA Kainate GLAST Glutamate-aspartate transporter GLT1 Glutamate transporter 1 mGluR Metabotropic glutamate receptors NCX Sodium-calcium exchanger NMDA N-Methyl-d-aspartate SN-6 2-[[4-[(4-Nitrophenyl)methoxy]phenyl] methyl]-4-thiazolidinecarboxylic acid ethyl ester Glutamate as neurotransmitterThe role of the glutamatergic neurotransmission into the human central nervous system (CNS) has been consolidated through a long research history over more than 70 years [1].The presence of high concentrations of glutamate in the brain was first identified in the 1930s, but at that time it was mainly considered an energy source for the CNS [2], as it has been ubiquitously found, with special regard to cytosolic and mitochondrial compartments. Only in 1984 was glutamate fully recognized as the major excitatory neurotransmitter in the mammalian brain [3] and now its functions within the CNS are well established. Glutamate is involved in many aspects of normal brain function, including cognition, memory and learning, cell migration, differentiation and death during the development of the CNS [4]. Furthermore, glutamate seems to have a role also in the peripheral nervous system and in endocrine cells as well [4,5]. Despite its ubiquitous nature, glutamate concentrations are maintained at homeostatic levels through the tightly Cellular and Molecular Life Sciences * Simona Magi

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