Up‐regulation of Na<sup>+</sup>–Ca<sup>2+</sup> exchange activity by interferon‐γ in cultured rat microglia

Nagano, Tadayoshi; Kawasaki, Yasushi; Baba, Akemichi; Takemura, Masashi; Matsuda, Takehisa

doi:10.1111/j.1471-4159.2004.02511.x

Cited by 42 publications

(31 citation statements)

References 38 publications

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“…Although we did not detect a change in their expression after inducing phagocytosis for one hour; pathological conditions, other stimuli and those acting over longer periods might affect exchanger expression. For instance, both NCX expression and Ca 2+ signaling were found to be transiently up-regulated after treatment with IFNg, 62 a cytokine implicated in CNS pathologies such as stroke. In future, it would be interesting to determine if TNFa and IL1b, which evoke chronic Ca 2+ elevations in microglia (reviewed in ref.…”

Section: Discussionmentioning

confidence: 99%

Reversed Na⁺/Ca²⁺Exchange Contributes to Ca²⁺Influx and Respiratory Burst in Microglia

Newell

Stanley²,

Schlichter

2007

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KEy WordSmicroglia activation, brain macrophage, reversed sodium-calcium exchange, Slc8a, NCX1-3, superoxide production, quantitative real-time RT-PCR, phagocytosis, Ca 2+ paradox, perforated patch, SBFI imaging, Fura-2 imaging AbSTrACTPhagocytosis and the ensuing NADPH-mediated respiratory burst are important aspects of microglial activation that require calcium ion (Ca 2+ ) influx. However, the specific Ca 2+ entry pathway(s) that regulates this mechanism remains unclear, with the best candidates being surface membrane Ca 2+ -permeable ion channels or Na + /Ca 2+ exchangers. In order to address this issue, we used quantitative real-time RT-PCR to assess mRNA expression of the Na + /Ca 2+ exchangers, Slc8a1-3/NCX1-3, before and after phagocytosis by rat microglia. All three Na + /Ca 2+ exchangers were expressed, with mRNA levels of NCX1 > NCX3 > NCX2, and were unaltered during the one hour phagocytosis period. We then carried out a biophysical characterization of Na + /Ca 2+ exchanger activity in these cells. To investigate conditions under which Na + /Ca 2+ exchange was functional, we used a combination of perforated patch-clamp analysis, fluorescence imaging of a Ca 2+ indicator (Fura-2) and a Na + indicator (SBFI), and manipulations of membrane potential and intracellular and extracellular ions. Then, we used a pharmacological toolbox to compare the contribution of Na + /Ca 2+ exchange with candidate Ca 2+ -permeable channels, to the NADPH-mediated respiratory burst that was triggered by phagocytosis. We find that inhibiting the reversed mode of the Na + /Ca 2+ exchanger with KB-R7943, dose dependently reduced the phagocytosis-stimulated respiratory burst; whereas, blockers of store-operated Ca 2+ channels or L-type voltage-gated Ca 2+ channels had no effect. These results provide evidence that Na + /Ca 2+ exchangers are potential therapeutic targets for reducing the bystander damage that often results from microglia activation in the damaged CNS. AbbrEviATioNSCR3, complement receptor 3; DPI, diphenylene iodonium; FBS, fetal bovine serum; HPRT1, hypoxanthine guanine phosphoribosyl transferase; IFNg, interferon-gamma; IL1b, interleukin 1 beta; NADPH, nicotinamide adenine dinucleotide phosphate; NCX, Na + / Ca 2+ exchanger; NMDG + , n-methyl d-glucamine; qRT-PCR, quantitative real-time reverse transcriptase polymerase chain reaction; SERCA, smooth endoplasmic reticulum calcium ATPase; SOC, store-operated Ca 2+ channels; TNFa, tumor necrosis factor alpha

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Section: Discussionmentioning

confidence: 99%

Reversed Na⁺/Ca²⁺Exchange Contributes to Ca²⁺Influx and Respiratory Burst in Microglia

Newell

Stanley²,

Schlichter

2007

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“…39 Interestingly, the expression of this antiporter can be altered under particular conditions, such as hypoxia. 9 Cerebral edema is known to exacerbate neuronal damage induced by ischemia.…”

Section: Discussionmentioning

confidence: 99%

Na ⁺ /Ca ²⁺ Exchanger Maintains Ionic Homeostasis in the Peri-Infarct Area

Tortiglione

Picconi

Barone

et al. 2007

Stroke

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Background and Purpose-A prominent feature of cerebral ischemia is the excessive intracellular accumulation of both Na ϩ and Ca 2ϩ ions, which results in subsequent cell death. The plasma membrane Na ϩ /Ca 2ϩ exchanger (NCX), regulates the distribution of these ions acting either in the forward mode or in its reverse mode and it can play a critical role in brain ischemia. However, it is unclear whether the activity of NCX leads to detrimental or beneficial effects. Methods-Extracellular field potentials and whole-cell patch clamp recordings were obtained from rat corticostriatal brain-slice preparations in the peri-infarct area 24 hours after the permanent middle cerebral artery occlusion. Ischemia was induced in rats by permanents middle cerebral artery occlusion. Results-Bepridil, an inhibitor of NCX, reduced in a concentration-dependent manner (IC 50 ϭ68 mol/L) the field potential amplitude recorded from the peri-infarct area of corticostriatal slices. Conversely, no change was observed in sham-operated animals. The effect of bepridil was mimicked by 5-(N-4-chlorobenzyl)-2Ј,4Ј-dimethylbenzamil (CB-DMB) (IC 50 ϭ6 mol/L), a more selective inhibitor of NCX. In whole-cell patch clamp experiments, bepridil and CB-DMB caused an inward current in spiny neurons recorded from the peri-infarct area but not in the same cells recorded from controls. Interestingly, cholinergic interneurons recorded from the striatal peri-infarct area did not develop an inward current after the application of NCX inhibitors, suggesting that the electrophysiological alterations induced by NCX inhibition are cell-type specific. Bepridil and CB-DMB also induced a suppression of excitatory synaptic currents in most of spiny neurons recorded from the peri-infarct area. This effect was not coupled to a significant change of paired-pulse facilitation suggesting a postsynaptic site of action. Conclusions-Our data indicate that NCX plays a critical role in the maintenance of ionic homeostasis in the peri-infarct area. ions are known to occur in pathophysiologic states, such as brain ischemia. [2][3][4][5][6][7][8][9] Moreover, a prominent feature of cerebral ischemia is the excessive extracellular accumulation of glutamate and subsequent impairment of intracellular Na ϩ and Ca 2ϩ homeostasis, which results in subsequent cell death. 3,10,11 Thus, by controlling intracellular homeostasis of these 2 ions, NCX may play a pivotal role in the events leading to ischemic damage. Reduction of the energy supply leads to a cascade of events including depolarization, influx of Na ϩ , and the subsequent reverse operation of the membrane protein that ultimately terminates in intracellular Ca 2ϩ overload and irreversible neuronal injury. 2,12 Conflicting reports have been published on the role played by NCX during brain ischemia. The inhibition of NCX prevents the activation of phospholipases that occurs after an ischemic insult of the brain. 13 Similarly, activation of NCX in its reverse mode plays an important role in cellular Ca 2ϩ Received November 24, 2006; ...

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“…All three NCX exchangers, NCX1, NCX2, and NCX3, are expressed in microglia, but NCX1 is the most prominent. 23,65 Na þ /Ca 2 þ exchanger activity in microglia was first recorded by Matsuda et al 66 who observed that a Na þ -dependent 45 Ca 2 þ uptake was inhibited by the NCX inhibitor SEA0400. Interestingly, NCX1 in microglia has a key role in response to interferon-g (IFN-g) and NO, 67 two cell products implicated in several CNS pathologies, including stroke.…”

Section: Namentioning

confidence: 99%

“…NBC, Na whereas MAP kinase and ERK are involved in the delayed increase in NCX activity. 65 Furthermore, Nagano et al showed that NCX is activated by NO and is involved in NO-induced depletion of Ca 2 þ in the endoplasmic reticulum,thus leading to endoplasmic reticulum stress. 67 The responses of NCX to IFN-g and NO implies that Ca 2 þ uptake via NCX operating in reverse mode may have a role for microglial activation under pathological conditions.…”

Section: Namentioning

confidence: 99%

Ionic Transporter Activity in Astrocytes, Microglia, and Oligodendrocytes During Brain Ischemia

Annunziato

Boscia

Pignataro

2013

J Cereb Blood Flow Metab

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Glial cells constitute a large percentage of cells in the nervous system. During recent years, a large number of studies have critically attributed to glia a new role which no longer reflects the long-held view that glia constitute solely a silent and passive supportive scaffolding for brain cells. Indeed, it has been hypothesized that glia, partnering neurons, have a much more actively participating role in brain function. Alteration of intraglial ionic homeostasis in response to ischemic injury has a crucial role in inducing and maintaining glial responses in the ischemic brain. Therefore, glial transporters as potential candidates in stroke intervention are becoming promising targets to enhance an effective and additional therapy for brain ischemia. In this review, we will describe in detail the role played by ionic transporters in influencing astrocyte, microglia, and oligodendrocyte activity and the implications that these transporters have in the progression of ischemic lesion.

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Up‐regulation of Na⁺–Ca²⁺ exchange activity by interferon‐γ in cultured rat microglia

Cited by 42 publications

References 38 publications

Reversed Na⁺/Ca²⁺Exchange Contributes to Ca²⁺Influx and Respiratory Burst in Microglia

Reversed Na⁺/Ca²⁺Exchange Contributes to Ca²⁺Influx and Respiratory Burst in Microglia

Na ⁺ /Ca ²⁺ Exchanger Maintains Ionic Homeostasis in the Peri-Infarct Area

Ionic Transporter Activity in Astrocytes, Microglia, and Oligodendrocytes During Brain Ischemia

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Up‐regulation of Na+–Ca2+ exchange activity by interferon‐γ in cultured rat microglia

Cited by 42 publications

References 38 publications

Reversed Na+/Ca2+Exchange Contributes to Ca2+Influx and Respiratory Burst in Microglia

Reversed Na+/Ca2+Exchange Contributes to Ca2+Influx and Respiratory Burst in Microglia

Na + /Ca 2+ Exchanger Maintains Ionic Homeostasis in the Peri-Infarct Area

Ionic Transporter Activity in Astrocytes, Microglia, and Oligodendrocytes During Brain Ischemia

Contact Info

Product

Resources

About

Up‐regulation of Na⁺–Ca²⁺ exchange activity by interferon‐γ in cultured rat microglia

Reversed Na⁺/Ca²⁺Exchange Contributes to Ca²⁺Influx and Respiratory Burst in Microglia

Reversed Na⁺/Ca²⁺Exchange Contributes to Ca²⁺Influx and Respiratory Burst in Microglia

Na ⁺ /Ca ²⁺ Exchanger Maintains Ionic Homeostasis in the Peri-Infarct Area