Evidence for a protective role played by the Na+/Ca2+ exchanger in cerebral ischemia induced by middle cerebral artery occlusion in male rats

Pignataro, Giuseppe; Tortiglione, Anna; Scorziello, Antonella; Giaccio, Lucia; Secondo, Agnese; Severino, Beatrice; Santagada, Vincenzo; Caliendo, Giuseppe; Amoroso, Salvatore; Renzo, Gianfranco Di; Annunziato, Lucio

doi:10.1016/j.neuropharm.2003.09.015

Cited by 93 publications

(97 citation statements)

References 33 publications

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“…Bepridil [105] and KB-R7943 [106] have been reported to directly block the NMDA channels in hippocampal neurons. KB-R7943 may also exert its actions by blocking L-type Ca 2+ channels [107] or, in vivo, via lowering the body temperature [108].…”

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

confidence: 99%

“…In the rat transient focal ischemia model, SEA0400 (3 mg/kg bolus followed by 2-hr infusion of 3 mg/ kg/hr) reduced infarction volume by ~50% in the cortex and by ~25% in the striatum [109]. In the rat permanent focal ischemia model, another group found potent protection with KB-R7943 (10 μg/kg delivered by osmotic minipump over 24 hrs) [108]. However, in the same study three other NCX blockers, bepridil, CB-DMB, and the NCX inhibitory peptide Glu-XIP, all significantly increased the infarction volume.…”

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

confidence: 99%

“…However, in the same study three other NCX blockers, bepridil, CB-DMB, and the NCX inhibitory peptide Glu-XIP, all significantly increased the infarction volume. The protective effect of KB-R7943 has been explained by its potent hypothermic actions [108]. Importantly, in vivo downregulation of NCX1 and NCX3, but not NCX2, using phosphorothioated antisense oligonucleotides, strongly increased infarction volumes and neurological deficits in a rat permanent focal ischemia model [110].…”

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: 99%

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

confidence: 99%

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 increase was blocked by the amiloride derivative CB-DMB [35,37]; it was not sensitive to the L-type Ca 21 -channel blocker nimodipine [40]; and it was markedly increased by blocking SERCA with thapsigargin [28,35]. The characteristics of Ca 21 signals in monocytes and macrophages resemble those found in other NCX-expressing cells such as primary neuronal cells [50] and BHK cells stably transfected with NCX1 and NCX3 [35]. The latter showed similar sensitivity of their NCX activity to CB-DMB (Secondo A. et al, unpublished data).…”

mentioning

confidence: 86%

“…All other reagents were from Carlo Erba (Milan, Italy). The amiloride derivative CB-DMB was synthesized as described previously [50]. BHK cells, WT or stably transfected with the canine cardiac NCX1, and rat brain NCX2 and NCX3 cDNAs were kindly donated by Dr. Bettina Linck (University of California, Los Angeles, CA) [32].…”

Section: Reagentsmentioning

confidence: 99%

Expression and function of Na⁺/Ca²⁺ exchangers 1 and 3 in human macrophages and monocytes

et al. 2009

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The Na 1 /Ca 21 exchanger (NCX) is a membrane transporter that can switch Na 1 and Ca 21 in either direction to maintain the homeostasis of intracellular Ca 21 . Three isoforms (NCX1, NCX2, and NCX3) have been characterized in excitable cells, e.g. neurons and muscle cells. We examined the expression of these NCX isoforms in primary human lung macrophages (HLM) and blood monocytes. NCX1 and NCX3, but not NCX2, are expressed in HLM and monocytes at both mRNA and protein levels. Na 1 -free medium induced a significant increase in intracellular calcium concentration ([Ca 21 ] i ) in both cell types. This response was completely abolished by the NCX inhibitor 5-(N-4-chlorobenzyl)-20,40-dimethylbenzamil (CB-DMB). Moreover, inhibition of NCX activity during Ca 21 -signaling induced by histamine caused a delay in restoring baseline [Ca 21 ] i . Na 1 -free medium induced TNF-a expression and release in HLM comparable to that caused by LPS. TNF-a release induced by Na 1 -free medium was blocked by CB-DMB and greatly reduced by RNAi-mediated knockdown of NCX1. These results indicate that human macrophages and monocytes express NCX1 and NCX3 that operate in a bidirectional manner to restore [Ca 21 ] i , to generate Ca 21 -signals, and to induce TNF-a production. Therefore, NCX may contribute to regulate Ca 21 homeostasis and proinflammatory functions in human macrophages and monocytes.Key words: Ca 21 -signaling . Macrophages . Monocytes . Na 1 /Ca 21 exchanger IntroductionThe Na 1 /Ca 21 exchanger (NCX) is a plasma membrane protein involved in the homeostasis of intracellular Ca 21 [1]. NCX is a bidirectional ion transporter that catalyzes the exchange of Na 1 and Ca 21 depending on their electrochemical gradients [2]. Under physiological conditions, NCX's primary role is to extrude Ca 21 from cells using the Na 1 gradient across the cell membrane (forward mode of operation) [3]. However, in some cases it can contribute to the Ca 21 influx into the cells by working in the reverse mode (i.e. coupling Ca 21 influx with Na 1 efflux) [4][5][6].Three isoforms of NCX, NCX1, NCX2, and NCX3 have been cloned in mammals, outlining a multigene family whose members share a similar molecular structure [7]. NCX is modeled with nine transmembrane segments involved in ion transport and a long central cytoplasmic loop that has regulatory functions [8]. However, truncated forms lacking certain transmembrane segments, but still possessing NCX activity, have also been Eur. J. Immunol. 2009. 39: 1405-1418 DOI 10.1002 Leukocyte signaling 1405 described as the result of alternative splicing of the three genes [9][10][11]. NCX1 is largely predominant in mammalian tissues such as heart, brain, and kidney while the expression of NCX2 and NCX3 appears to be limited to the brain and skeletal muscle [7]. NCX is a key element regulating intracellular Ca 21 concentrations ([Ca 21 ] i ) in many excitable cells, including myocardiocytes, retinal rod photoreceptors, smooth muscle cells, and neurons [3]. Non-excitable cells such as renal epithelial ce...

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Role of the Na⁺/Ca²⁺ exchanger in calcium homeostasis and human sperm motility regulation

Krasznai

Morisawa²,

Bazsáné

et al. 2005

Cell Motil. Cytoskeleton

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A number of cell functions, such as flagellar beating, swimming velocity, acrosome reaction, etc., are triggered by a Ca2+ influx across the cell membrane. For appropriate physiological functions, the motile human sperm maintains the intracellular free calcium concentration ([Ca2+]i) at a submicromolar level. The objective of this study was to determine the role of the Na+/Ca2+ exchanger (NCX) in the maintenance of [Ca2+]i in human spermatozoa. Spermatozoa maintained in extracellular medium containing>or=1 microM Ca2+ exhibited motility similar to that of the control. In addition to several calcium transport mechanisms described earlier, we provide evidence that the NCX plays a crucial role in the maintenance of [Ca2+]i. Three chemically unrelated inhibitors of the NCX (bepridil, DCB (3',4'-dichlorobenzamil hydrochloride), and KB-R7943) all blocked human sperm motility in a dose and incubation time dependent manner. The IC50 values for bepridil, DCB, and KB-R7943 were 16.2, 9.8, and 5.3 microM, respectively. The treatment with the above-mentioned blockers resulted in an elevated [Ca2+]i and a decreased [Na+]i. The store-operated calcium channel (SOCC) inhibitor SKF 96365 also blocked the sperm motility (IC50=2.44 microM). The presence of the NCX antigen in the human spermatozoa was proven by flow cytometry, confocal laser scanning microscopy, and immunoblotting techniques. Calcium homeostasis of human spermatozoa is maintained by several transport proteins among which the SOCC and the NCX may play a major role.

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Evidence for a protective role played by the Na+/Ca2+ exchanger in cerebral ischemia induced by middle cerebral artery occlusion in male rats

Cited by 93 publications

References 33 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

Expression and function of Na⁺/Ca²⁺ exchangers 1 and 3 in human macrophages and monocytes

Role of the Na⁺/Ca²⁺ exchanger in calcium homeostasis and human sperm motility regulation

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Evidence for a protective role played by the Na+/Ca2+ exchanger in cerebral ischemia induced by middle cerebral artery occlusion in male rats

Cited by 93 publications

References 33 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

Expression and function of Na+/Ca2+ exchangers 1 and 3 in human macrophages and monocytes

Role of the Na+/Ca2+ exchanger in calcium homeostasis and human sperm motility regulation

Contact Info

Product

Resources

About

Expression and function of Na⁺/Ca²⁺ exchangers 1 and 3 in human macrophages and monocytes

Role of the Na⁺/Ca²⁺ exchanger in calcium homeostasis and human sperm motility regulation