Essential role of the Na+-Ca2+ exchanger (NCX) in glutamate-enhanced cell survival in cardiac cells exposed to hypoxia/reoxygenation

Maiolino, Marta; Castaldo, Pasqualina; Lariccia, Vincenzo; Piccirillo, Silvia; Amoroso, Salvatore; Magi, Simona

doi:10.1038/s41598-017-13478-x

Cited by 38 publications

(36 citation statements)

References 56 publications

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“…Under both physiological and pathological conditions glutamate can contribute to cellular energy balance as substrate for anaplerotic reactions, and we demonstrated that NCX1 provides functional support for both glutamate uptake and ATP synthesis 10 , 11 , 19 . Therefore, we investigated whether the protective effect of glutamate could be ascribed to its potential to sustain ATP synthesis.…”

Section: Resultsmentioning

confidence: 73%

“…It is well established that EAATs mediate the high-affinity uptake of glutamate. We demonstrated that under both physiological and pathological conditions 10 , 11 , 19 , glutamate entry into the cells through EAAT3 is functionally related to NCX1 activity 10 , 11 . Therefore, once established that NCX1 was essential to mitigate cell injury, we explored whether EAAT3 activity could also be mandatorily required.…”

Section: Resultsmentioning

confidence: 88%

“…To explore the specific contribution of NCX1, we first used a pharmacological approach. When cells were exposed to the selective NCX inhibitor 2-[[4-[(4Nitrophenyl) methoxy] phenyl] methyl]-4-thiazolidinecarboxylic acid ethyl ester (SN-6, 1 µM) 19 , 20 , glutamate was wholly ineffective in protecting cells from H/R injury (Fig. 2a, b ).…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, once established that NCX1 was essential to mitigate cell injury, we explored whether EAAT3 activity could also be mandatorily required. We initially used the non-transportable EAAT blocker dl -threo-β-benzyloxyaspartic acid (DL-TBOA) 22 at the concentration of 300 µM 19 . It has been shown that DL-TBOA inhibits ischemia-evoked glutamate release, which has been ascribed to EAATs reverse mode of action 23 .…”

Section: Resultsmentioning

confidence: 99%

“…We previously found that under normoxia glutamate can increase ATP levels in neuronal and glial cells 10 , 11 . Interestingly, we recently demonstrated that in cardiomyocytes, glutamate can sustain cell metabolism also in a setting of H/R 19 . In both cases glutamate effect requires NCX activity.…”

Section: Discussionmentioning

confidence: 99%

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Glutamate as a potential “survival factor” in an in vitro model of neuronal hypoxia/reoxygenation injury: leading role of the Na+/Ca2+ exchanger

et al. 2018

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In brain ischemia, reduction in oxygen and substrates affects mitochondrial respiratory chain and aerobic metabolism, culminating in ATP production impairment, ionic imbalance, and cell death. The restoration of blood flow and reoxygenation are frequently associated with exacerbation of tissue injury, giving rise to ischemia/reperfusion (I/R) injury. In this setting, the imbalance of brain bioenergetics induces important metabolic adaptations, including utilization of alternative energy sources, such as glutamate. Although glutamate has long been considered as a neurotoxin, it can also be used as intermediary metabolite for ATP synthesis, and both the Na+/Ca2+ exchanger (NCX) and the Na+-dependent excitatory amino-acid transporters (EAATs) are essential in this pathway. Here we analyzed the role of NCX in the potential of glutamate to improve metabolism and survival of neuronal cells subjected to hypoxia/reoxygenation (H/R). In SH-SY5Y neuroblastoma cells differentiated into a neuron-like state, H/R produced a significant cell damage, a decrease in ATP cellular content, and intracellular Ca2+ alterations. Exposure to glutamate at the onset of the reoxygenation phase attenuated H/R-induced cell damage and evoked a significant raise in intracellular ATP levels. Furthermore, we found that in H/R cells NCX reverse-mode activity was reduced, and that glutamate limited such reduction. All the effects induced by glutamate supplementation were lost when cells were transfected with small interfering RNA against NCX1 and EAAT3, suggesting the need of a specific functional interplay between these proteins for glutamate-induced protection. Collectively, our results revealed the potential beneficial effect of glutamate in an in vitro model of H/R injury and focused on the essential role exerted by NCX1. Although preliminary, these findings could be a starting point to further investigate in in vivo systems such protective effect in ischemic settings, shedding a new light on the classical view of glutamate as detrimental factor.

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Section: Resultsmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Glutamate as a potential “survival factor” in an in vitro model of neuronal hypoxia/reoxygenation injury: leading role of the Na+/Ca2+ exchanger

et al. 2018

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Intracellular Calcium and Ischemic Damage: Dual Role of the Na+/Ca2+ Exchanger

Magi

Castaldo

Lariccia

et al. 2020

The First Outstanding 50 Years of “Università Politecnica Delle Marche”

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of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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

Magi

Piccirillo

Amoroso

2019

Cell. Mol. Life Sci.

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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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Essential role of the Na+-Ca2+ exchanger (NCX) in glutamate-enhanced cell survival in cardiac cells exposed to hypoxia/reoxygenation

Cited by 38 publications

References 56 publications

Glutamate as a potential “survival factor” in an in vitro model of neuronal hypoxia/reoxygenation injury: leading role of the Na+/Ca2+ exchanger

Glutamate as a potential “survival factor” in an in vitro model of neuronal hypoxia/reoxygenation injury: leading role of the Na+/Ca2+ exchanger

Intracellular Calcium and Ischemic Damage: Dual Role of the Na+/Ca2+ Exchanger

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

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