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

Rossana Sirabella, Agnese Secondo, Anna Pannaccione, Pasquale Molinaro, Luigi Formisano, Natascia Guida, Gianfranco Di Renzo, Lucio Annunziato, Mauro Cataldi

Research output: Contribution to journalArticlepeer-review

Abstract

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 extracellular-signal-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 down-regulation 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 MAPK-dependent regulation of NCX expression and activity which could be relevant in mediating some of the effects of MAPKs in neurons.

Original languageEnglish
Pages (from-to)911-922
Number of pages12
JournalJournal of Neurochemistry
Volume122
Issue number5
DOIs
Publication statusPublished - Sep 2012

Keywords

  • CREB1
  • ERK1/2
  • JNK
  • p38
  • Sodium/Calcium exchanger (NCX)
  • Sp1

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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