Pharmacology of Brain Na<sup>+</sup>/Ca<sup>2+</sup>Exchanger: From Molecular Biology to Therapeutic Perspectives

Annunziato, Lucio; Pignataro, Giuseppe; Renzo, G. F. Di

doi:10.1124/pr.56.4.5

Cited by 278 publications

(254 citation statements)

References 179 publications

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“…Despite evidence that the activity of the NCX reduces with age in both the reverse and forward modes (Canzoniero, et al, 1992, Michaelis, et al, 1984, to our knowledge, this is the first report of an age- (Annunziato, et al, 2004). Interestingly, this region is also responsive to reactive oxygen species (ROS), which as well as being implicated in neuronal aging of vertebrate species, may play a role in changes to neuronal excitability in certain neurons of the Lymnaea CNS (Watson, et al, 2012a).…”

Section: Ncx Mode Reversal May Contribute To the Age-related Changes mentioning

confidence: 80%

“…Indeed, lower levels of the antioxidant glutathione have been observed in the nervous system of older Lymnaea . Second, there may have been a shift in the concentration of intracellular ionic species, for example a high [Na + ]i or low [Ca 2+ ]i (Annunziato, et al, 2004), driving the NCX to work in reverse mode. An increase in the [Na + ]i may occur as a result of an age-related reduction in the activity of Na + /K + ATPase.…”

Section: Ncx Mode Reversal May Contribute To the Age-related Changes mentioning

confidence: 99%

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A switch in the mode of the sodium/calcium exchanger underlies an age-related increase in the slow afterhyperpolarization

Scutt

Allen

Kemenes

et al. 2015

Neurobiology of Aging

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During aging, the Ca 2+ sensitive slow afterhyperpolarization (sAHP) of hippocampal neurons is known to increase in duration. This change has also been observed in the serotonergic cerebral giant cells (CGCs) of the pond snail Lymnaea stagnalis, but has yet to be characterized. In this paper, we confirm that there is a reduction in firing rate, an increase in the duration of the sAHP, and an alteration in the strength and speed of spike frequency adaptation (SFA) in the CGCs during aging, a finding that is compatible with an increase in a sAHP current. We go on to show that age-related changes in the kinetics of SFA are consistent with a reduction in Ca 2+ clearance from the cell, which we confirm with Ca 2+ imaging and pharmacological manipulation of the sodium calcium exchanger (NCX). These experiments suggest that the NCX may be switching to a reverse-mode configuration in the CGCs during aging.3

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Section: Ncx Mode Reversal May Contribute To the Age-related Changes mentioning

confidence: 80%

Section: Ncx Mode Reversal May Contribute To the Age-related Changes mentioning

confidence: 99%

A switch in the mode of the sodium/calcium exchanger underlies an age-related increase in the slow afterhyperpolarization

Scutt

Allen

Kemenes

et al. 2015

Neurobiology of Aging

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“…Effect of Na 1 -free solution on [Ca 21 ] i in HLM and monocytes NCX can operate in two directions depending on the transmembrane gradient of Na 1 and Ca 21 ions [2]. NCX activity was initially evaluated in the reverse mode of operation elicited by exposing the cells to a single pulse of Na 1 -free medium [35].…”

Section: Expression Of Ncx1 Ncx2 and Ncx3 In Hlm And Blood Monocytesmentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

“…In this context, the role of NCX in macrophages and monocytes might be particularly important since NCX3, and partially NCX1, are not dependent on ATP for their function [35]. This means that NCX can contribute to maintaining [Ca 21 ] i homeostasis also in pathophysiological conditions such as tissue ischemia or anoxia in which ATP levels are reduced and the other Ca 21 buffering systems are impaired [2,35]. For example, chronic lung inflammation often leads to severe tissue hypoxia, which is frequently accompanied by ionic dysregulation [51].…”

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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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Targeting Na⁺/Ca²⁺Exchange as an Antiarrhythmic Strategy

Antoons

Willems

Sipido

2009

Novel Therapeutic Targets for Antiarrhythmic Drugs

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Pharmacology of Brain Na⁺/Ca²⁺Exchanger: From Molecular Biology to Therapeutic Perspectives

Cited by 278 publications

References 179 publications

A switch in the mode of the sodium/calcium exchanger underlies an age-related increase in the slow afterhyperpolarization

A switch in the mode of the sodium/calcium exchanger underlies an age-related increase in the slow afterhyperpolarization

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

Targeting Na⁺/Ca²⁺Exchange as an Antiarrhythmic Strategy

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Pharmacology of Brain Na+/Ca2+Exchanger: From Molecular Biology to Therapeutic Perspectives

Cited by 278 publications

References 179 publications

A switch in the mode of the sodium/calcium exchanger underlies an age-related increase in the slow afterhyperpolarization

A switch in the mode of the sodium/calcium exchanger underlies an age-related increase in the slow afterhyperpolarization

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

Targeting Na+/Ca2+Exchange as an Antiarrhythmic Strategy

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Product

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Pharmacology of Brain Na⁺/Ca²⁺Exchanger: From Molecular Biology to Therapeutic Perspectives

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

Targeting Na⁺/Ca²⁺Exchange as an Antiarrhythmic Strategy