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First published on December 13, 2007; DOI: 10.1124/mol.107.042549

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Received for publication October 9, 2007.
Revised December 12, 2007.
Accepted for publication December 12, 2007.

The two isoforms of the Na+/Ca2+ exchanger, NCX1 and NCX3, constitute novel additional targets for the pro-survival action of Akt/PKB pathway

Luigi Formisano 1, Mariangela Saggese 1, Agnese Secondo 1, Rossana Sirabella 1, Pasquale Vito 2, Valeria Valsecchi 1, Pasquale Molinaro 1, Gianfranco Di Renzo 1, Lucio Annunziato 1*

1 University of Naples Federico II 2 University of Sannio

* Address correspondence to: E-mail: lannunzi{at}unina.it

Abstract

The proteins NCX1, NCX2 and NCX3 expressed on the plasma membrane of neurons play a crucial role in the ionic regulation as they are the major bidirectional system promoting the efflux and influx of Na+ and Ca2+ ions. Here we demonstrate that NCX1 and NCX3 proteins are novel additional targets for the survival action of the PI3-K/Akt pathway. Indeed, the doxycycline-dependent over-expression of constitutively active Akt1 in Tet-Off PC-12 positive mutants and the exposure of Tet-Off PC-12 wild type to NGF induced an up-regulation of NCX1 and NCX3 proteins. NCX1 up-regulation induced by Akt1 activation occurred at the transcriptional level since NCX1 mRNA increased and it was counteracted by CREB1 inhibition through siRNA strategy. In contrast, Akt1-induced NCX3 up-regulation recognized a post transcriptional mechanism occurring at the proteasome level since (1) NCX3 transcript did not increase and (2) the proteasome inhibitor MG-132 did not further enhance NCX3 protein levels in Akt1 active mutants as it would be expected if the ubiquitin-proteasome complex was not already blocked by Akt1 pathway. As expected, in PC-12 Tet-Off wild type cells MG-132 enhanced NCX3 protein levels. This up-regulation produced an increased activity of NCX function. Furthermore NCX1 and NCX3 up-regulation contributed to the survival action of Akt1 during chemical hypoxia since, both the silencing of NCX1 or NCX3 and the pharmacological paninhibition of NCX isoforms reduced the pro-survival property of Akt1. Together, these results indicated that NCX1 and NCX3 represent novel additional molecular targets for the pro-survival action of PI-3K/Akt pathway.


Key words: NGF/EGF, CREB, Regulation of gene expression, Overexpression, RNA/siRNA, Protein synthesis inhibitors, Ischemia/Reperfusion




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