Decreased Neuronal Death in Na+/H+Exchanger Isoform 1-Null Mice afterIn VitroandIn VivoIschemia

Luo, Jing; Chen, Hai; Kintner, Douglas B.; Shull, Gary E.; Sun, Dandan

doi:10.1523/jneurosci.3271-05.2005

Cited by 110 publications

(188 citation statements)

References 57 publications

(58 reference statements)

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“…In the same paradigm HOE-642 also potently suppressed neuronal death. Cytosolic Na + and Ca + overload and the effects of HOE-642 were blunted in the neurons prepared from NHE1 −/− animals [102]. Cultured astrocytes typically do not die when subjected to hypoxia-glucose deprivation.…”

Section: Pathological Roles For Na + /H + Exchange: Impact On [Na + ]mentioning

confidence: 89%

“…In cultured cortical neurons, oxygen-glucose deprivation followed by the reoxygenation causes steep rises in [Na + ] i and [Ca 2+ ] i that is potently inhibited by the selective NHE1 blocker 1 μM HOE-642 [102]. In the same paradigm HOE-642 also potently suppressed neuronal death.…”

Section: Pathological Roles For Na + /H + Exchange: Impact On [Na + ]mentioning

confidence: 96%

“…30 min before ischemia) protected hippocampal neurons and reduced neurological deficits in the gerbil global ischemia model [100], and reduced the ischemic release of excitotoxins in the rat global ischemia (25 μM, applied topically in the cortex) [101]. In a mouse transient focal ischemia model, inhibition of NHE1 with selective blocker HOE-642 (1 mg/kg i.v., 5 min prior ischemia), or a decrease in the NHE1 expression in heterozygous NHE1 +/− animals, both significantly reduced brain infarction by ~30% and tended to suppress the development of brain edema [102]. The NHE1 −/− animals have very high mortality rates and therefore could not be used in ischemia studies.…”

Section: Pathological Roles For Na + /H + Exchange: Impact On [Na + ]mentioning

confidence: 99%

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Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

Mongin

2007

Pathophysiology

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The mechanisms of brain tissue damage in stroke are strongly linked to the phenomenon of excitotoxicity, which is defined as damage or death of neural cells due to excessive activation of receptors for the excitatory neurotransmitters glutamate and aspartate. Under physiological conditions, ionotropic glutamate receptors mediate the processes of excitatory neurotransmission and synaptic plasticity. In ischemia, sustained pathological release of glutamate from neurons and glial cells causes prolonged activation of these receptors, resulting in massive depolarization and cytoplasmic Ca 2+ overload. The NMDA subtype of glutamate receptors is particularly important as it represents the main initial route for the Ca 2+ influx. High cytoplasmic levels of Ca 2+ activate many degradative processes that, depending on the metabolic status, cause immediate or delayed death of neural cells. This traditional view has been expanded by a number of observations that implicate Cl − channels and several types of non-channel transporter proteins, such as the Na + ,K + ,2Cl − cotransporter, Na + /H + exchanger, and Na + /Ca 2+ exchanger, in the development of glutamate toxicity. Some of these ion transporters increase tissue damage by promoting pathological cell swelling and necrotic cell death, while others contribute to a long term accumulation of cytoplasmic Ca 2+ . This brief review is aimed at illustrating how the dysregulation of various ion transport processes combine in a 'perfect storm' that disrupts neural ionic homeostasis and culminates in the irreversible damage and death of neural cells. The clinical relevance of individual transporters as targets for therapeutic intervention in stroke is also briefly discussed.

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Section: Pathological Roles For Na + /H + Exchange: Impact On [Na + ]mentioning

confidence: 89%

Section: Pathological Roles For Na + /H + Exchange: Impact On [Na + ]mentioning

confidence: 96%

Section: Pathological Roles For Na + /H + Exchange: Impact On [Na + ]mentioning

confidence: 99%

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Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

Mongin

2007

Pathophysiology

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“…Enhanced NHE1 activity in these pathological situations causes substantial intracellular Na + accumulation. This activates the plasmalemmal Na + /Ca ++ exchanger inducing a deleterious increase of intracellular Ca ++ that triggers various pathways ultimately leading to cell death [74,99,98,77]. Genetic ablation or pharmalogic inhibition of NHE1 during episodes of ischemiareperfusion mitigated cardiac and neural injuries both in vivo and in vitro in rodents and pigs [85,32,62].…”

Section: Slc9a1-nhe1mentioning

confidence: 99%

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

Fuster

Alexander

2013

Pflugers Arch - Eur J Physiol

137

122

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The SLC9 gene family encodes Na + /H + exchangers (NHEs). These transmembrane proteins transport ions across lipid bilayers in a diverse array of species from prokaryotes to eukaryotes, including plants, fungi and animals. They utilize the electrochemical gradient of one ion to transport another ion against its electrochemical gradient. Currently, 13 evolutionarily conserved NHE isoforms are known in mammals [46,22,128]. The SLC9 gene family (solute carrier classification of transporters:www.bioparadigms.org) is divided into three subgroups [46]. The SLC9A subgroup encompasses plasmalemmal isoforms NHE1-5 (SLC9A1-5) and the predominantly intracellular isoforms NHE6-9 (SLC9A6-9). The SLC9B subgroup consists of two recently cloned isoforms, NHA1 and NHA2 (SLC9B1 and SLC9B2, respectively). The SLC9C subgroup consist of a sperm specific plasmalemmal NHE (SLC9C1) and a putative NHE, SLC9C2, for which there is currently no functional data [46].NHEs participate in the regulation of cytosolic and organellar pH as well as cell volume. In the intestine and kidney, NHEs are critical for transepithelial movement of Na + and HCO 3 -and thus for whole body volume and acid-base homeostasis [46]. Mutations in the NHE6 or NHE9 genes cause neurological disease in humans and are currently the only NHEs directly linked to human disease.However, it is becoming increasingly apparent that members of this gene family contribute to the pathophysiology of multiple human diseases.

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“…To date, nine NHE isoforms (NHE1-9) have been cloned in mammalian tissues (1). Na ϩ /H ϩ exchanger isoform 1 (NHE1) is the most abundant NHE isoform in the rat central nervous system (2) and crucial in regulation of neuronal pH i (3,4). We have recently reported that NHE1 activity plays an important role in neuronal damage in both in vitro and in vivo ischemic models (4).…”

mentioning

confidence: 99%

ERK1/2-p90RSK-mediated Phosphorylation of Na+/H+ Exchanger Isoform 1

Luo

Kintner

Shull

et al. 2007

Journal of Biological Chemistry

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The function and regulation of Na ؉ /H ؉ exchanger isoform 1 (NHE1) following cerebral ischemia are not well understood. In this study, we demonstrate that extracellular signal-related kinases (ERK1/2) play a role in stimulation of neuronal NHE1 following in vitro ischemia. NHE1 activity was significantly increased during 10 -60 min reoxygenation (REOX) after 2-h oxygen and glucose deprivation (OGD). OGD/REOX not only increased the V max for NHE1 but also shifted the K m toward decreased [H ؉ ] i . These changes in NHE1 kinetics were absent when MAPK/ERK kinase (MEK) was inhibited by the MEK inhibitor U0126. There were no changes in the levels of phosphorylated ERK1/2 (p-ERK1/2) after 2 h OGD. The p-ERK1/2 level was significantly increased during 10 -60 min REOX, which was accompanied by nuclear translocation. U0126 abolished REOX-induced elevation and translocation of p-ERK1/2. We further examined the ERK/90-kDa ribosomal S6 kinase (p90 RSK ) signaling pathways. At 10 min REOX, phosphorylated NHE1 was increased with a concurrent elevation of phosphorylation of p90 RSK , a known NHE1 kinase. Inhibition of MEK activity with U0126 abolished phosphorylation of both NHE1 and p90 RSK . Moreover, neuroprotection was observed with U0126 or genetic ablation or pharmacological inhibition of NHE1 following OGD/REOX. Taken together, these results suggest that activation of ERK1/2-p90 RSK pathways following in vitro ischemia phosphorylates NHE1 and increases its activity, which subsequently contributes to neuronal damage. The Naϩ /H ϩ exchanger (NHE) 2 family is a group of membrane transport proteins that catalyzes the secondary active electroneurtral exchange of one Na ϩ for one H ϩ . To date, nine NHE isoforms (NHE1-9) have been cloned in mammalian tissues (1). Na ϩ /H ϩ exchanger isoform 1 (NHE1) is the most abundant NHE isoform in the rat central nervous system (2) and crucial in regulation of neuronal pH i (3, 4). We have recently reported that NHE1 activity plays an important role in neuronal damage in both in vitro and in vivo ischemic models (4). Inhibition of NHE1 activity during OGD/REOX prevents intracellular Na ϩ and Ca 2ϩ overload and thus reduces the Ca 2ϩ -mediated cascade of deleterious events (4). In acutely isolated CA1 neurons, an anoxia-triggered intracellular alkalization depends on activation of NHE1 (5). We also found that NHE1 activity is stimulated in cortical astrocytes following in vitro ischemia (6). However, whether NHE1 activity is overstimulated in cortical neurons following in vitro ischemia remains unknown.NHE1 has two large functional domains. The N-terminal transmembrane domain (ϳ500 amino acids) is responsible for cation translocation, and the cytoplasmic C-terminal domain (ϳ315 amino acids) is the main regulatory site for the NHE1 activity (7). The distal C-terminal tail of NHE1 contains a number of serine and threonine residues that are phosphorylated by several protein kinases, including extracellular signal-related kinases (ERK1/2) and 90-kDa ribosomal S6 kinase (p90 RSK ) (8). Activa...

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Decreased Neuronal Death in Na⁺/H⁺Exchanger Isoform 1-Null Mice afterIn VitroandIn VivoIschemia

Cited by 110 publications

References 57 publications

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

ERK1/2-p90RSK-mediated Phosphorylation of Na+/H+ Exchanger Isoform 1

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