The Na + /Ca 2+ Exchanger: A Target for Therapeutic Intervention in Cerebral Ischemia

Annunziato, Lucio; Molinaro, Pasquale; Secondo, Agnese; Pannaccione, Anna; Scorziello, Antonella; Pignataro, Giuseppe; Cuomo, Ornella; Sirabella, Rossana; Boscia, Francesca; Spinali, Alessandra; Renzo, Gianfranco Di

doi:10.1007/978-1-60761-280-3_5

Cited by 3 publications

(4 citation statements)

References 73 publications

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“…Although the ncx2 promoter has not been identified yet (Annunziato et al 2009), ChIP experiments showed that CREB1 binds to two different sequences that had been previously identified in a genome-wide search for putative CRE sequences in proximity of ncx2 TSS. Collectively, the results of the siRNA and ChIP experiments suggest that CREB1 could be among the transcription factors regulating ncx2 gene transcription.…”

Section: Discussionmentioning

confidence: 99%

“…Although the ncx2 promoter has not been identified yet (Annunziato et al. 2009), ChIP experiments showed that CREB1 binds to two different sequences that had been previously identified in a genome‐wide search for putative CRE sequences in proximity of ncx2 TSS.…”

Section: Discussionmentioning

confidence: 99%

“…2008). Because of the pathophysiological relevance of NCX in the brain, great efforts have been devoted to the identification of mechanisms regulating its expression both under normal conditions and in experimental models of neurological disorders (Annunziato et al. , 2004, 2009).…”

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confidence: 99%

“…In addition, NCX also controls neuronal survival after ischemic insults, as indicated by the evidence that ischemic brain damage is significantly increased by the knocking-down or silencing of NCX1 or NCX3 Molinaro et al 2008). Because of the pathophysiological relevance of NCX in the brain, great efforts have been devoted to the identification of mechanisms regulating its expression both under normal conditions and in experimental models of neurological disorders (Annunziato et al, 2004(Annunziato et al, , 2009. In this framework, we here hypothesized whether NCX isoform expression and activity could be regulated by mitogenactivated protein kinases (MAPKs), a family of Ser/Thr kinases transducing a large array of extracellular signals (Avruch 2007).…”

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ERK1/2, p38, and JNK regulate the expression and the activity of the three isoforms of the Na⁺/Ca²⁺exchanger, NCX1, NCX2, and NCX3, in neuronal PC12 cells

Sirabella

Secondo²,

Pannaccione³

et al. 2012

Journal of Neurochemistry

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We evaluated whether changes in expression and activity of the three sodium/calcium exchanger isoforms, NCX1, NCX2, and NCX3 occurred in PC12 cells when the extracellularsignal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK), and p38 mitogen-activated protein kinases (MAPKs) were silenced, pharmacologically blocked, or activated with nerve growth factor (NGF). Several findings suggesting that MAPKs control NCX emerged: (1) A decrease in NCX1 and NCX3 basal expression occurred when JNK or MEK1, the extracellular-signal-regulated kinases 1/2 upstream activator, were pharmacologically blocked, respectively; (2) NGF increased cAMP response element-binding 1 (CREB1) and Specificity Protein 1 (Sp1) binding to ncx1 promoter and CREB1 binding to two different sequences close to ncx2 transcription start site on genomic DNA; (3) An up-regulation of NCX1 and NCX3, abrogated upon either MEK1 or p38 blockade, and a down-regulation of NCX2, abolished upon p38 blockade, occurred upon NGF-induced MAPK activation. The NCX1 up-regulation was abolished upon either CREB1 or Sp1 silencing, whereas NCX2 downregulation was abrogated only by CREB1 silencing. The NCX3 up-regulation was unaffected by CREB1 or Sp1 silencing and abolished upon proteasomal inhibition; (4) Whole-cell Na + /Ca 2+ exchange decreased when MEK1 and JNK were blocked and increased when MAPKs were activated by NGF. Collectively, these results demonstrate a MAPKdependent regulation of NCX expression and activity which could be relevant in mediating some of the effects of MAPKs in neurons.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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ERK1/2, p38, and JNK regulate the expression and the activity of the three isoforms of the Na⁺/Ca²⁺exchanger, NCX1, NCX2, and NCX3, in neuronal PC12 cells

Sirabella

Secondo²,

Pannaccione³

et al. 2012

Journal of Neurochemistry

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Transcriptional Regulation of ncx1 Gene in the Brain

Valsecchi

Pignataro

Sirabella

et al. 2012

Advances in Experimental Medicine and Biology

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The ubiquitous sodium-calcium exchanger isoform 1 (NCX1) is a -bidirectional transporter that plays a relevant role under physiological and pathophysiological conditions including brain ischemia by regulating intraneuronal Ca(2+) and Na(+) homeostasis. Although changes in ncx1 protein and transcript expression have been detected during stroke, its transcriptional regulation is still largely unexplored. Here, we reviewed our recent findings on several transcription factors including cAMP response element-binding protein (CREB), nuclear factor kappa B (NF-κB), and hypoxia-inducible factor-1 (HIF-1) in the control of the ncx1 gene expression in neuronal cells.

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Neurounina-1, a Novel Compound That Increases Na⁺/Ca²⁺Exchanger Activity, Effectively Protects against Stroke Damage

Molinaro

Cantile²,

Cuomo³

et al. 2012

Mol Pharmacol

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Previous studies have demonstrated that the knockdown or knockout of the three Na 1 /Ca 21 exchanger (NCX) isoforms, NCX1, NCX2, and NCX3, worsens ischemic brain damage. This suggests that the activation of these antiporters exerts a neuroprotective action against stroke damage. However, drugs able to increase the activity of NCXs are not yet available. We have here succeeded in synthesizing a new compound, named neurounina-1 (7-nitro-5-, provided with an high lipophilicity index and able to increase NCX activity. Ca 21 radiotracer, Fura-2 microfluorimetry, and patchclamp techniques revealed that neurounina-1 stimulated NCX1 and NCX2 activities with an EC 50 in the picomolar to low nanomolar range, whereas it did not affect NCX3 activity. Furthermore, by using chimera strategy and site-directed mutagenesis, three specific molecular determinants of NCX1 responsible for neurounina-1 activity were identified in the a-repeats. Interestingly, NCX3 became responsive to neurounina-1 when both a-repeats were replaced with the corresponding regions of NCX1. In vitro studies showed that 10 nM neurounina-1 reduced cell death of primary cortical neurons exposed to oxygen-glucose deprivation followed by reoxygenation. Moreover, in vitro, neurounina-1 also reduced gaminobutyric acid (GABA) release, enhanced GABA A currents, and inhibited both glutamate release and N-methyl-D-aspartate receptors. More important, neurounina-1 proved to have a wide therapeutic window in vivo. Indeed, when administered at doses of 0.003 to 30 mg/kg i.p., it was able to reduce the infarct volume of mice subjected to transient middle cerebral artery occlusion even up to 3 to 5 hours after stroke onset. Collectively, the present study shows that neurounina-1 exerts a remarkable neuroprotective effect during stroke and increases NCX1 and NCX2 activities.

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The Na + /Ca 2+ Exchanger: A Target for Therapeutic Intervention in Cerebral Ischemia

Cited by 3 publications

References 73 publications

ERK1/2, p38, and JNK regulate the expression and the activity of the three isoforms of the Na⁺/Ca²⁺exchanger, NCX1, NCX2, and NCX3, in neuronal PC12 cells

ERK1/2, p38, and JNK regulate the expression and the activity of the three isoforms of the Na⁺/Ca²⁺exchanger, NCX1, NCX2, and NCX3, in neuronal PC12 cells

Transcriptional Regulation of ncx1 Gene in the Brain

Neurounina-1, a Novel Compound That Increases Na⁺/Ca²⁺Exchanger Activity, Effectively Protects against Stroke Damage

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The Na + /Ca 2+ Exchanger: A Target for Therapeutic Intervention in Cerebral Ischemia

Cited by 3 publications

References 73 publications

ERK1/2, p38, and JNK regulate the expression and the activity of the three isoforms of the Na+/Ca2+exchanger, NCX1, NCX2, and NCX3, in neuronal PC12 cells

ERK1/2, p38, and JNK regulate the expression and the activity of the three isoforms of the Na+/Ca2+exchanger, NCX1, NCX2, and NCX3, in neuronal PC12 cells

Transcriptional Regulation of ncx1 Gene in the Brain

Neurounina-1, a Novel Compound That Increases Na+/Ca2+Exchanger Activity, Effectively Protects against Stroke Damage

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ERK1/2, p38, and JNK regulate the expression and the activity of the three isoforms of the Na⁺/Ca²⁺exchanger, NCX1, NCX2, and NCX3, in neuronal PC12 cells

ERK1/2, p38, and JNK regulate the expression and the activity of the three isoforms of the Na⁺/Ca²⁺exchanger, NCX1, NCX2, and NCX3, in neuronal PC12 cells

Neurounina-1, a Novel Compound That Increases Na⁺/Ca²⁺Exchanger Activity, Effectively Protects against Stroke Damage