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.

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 ERK1/2, JNK, and p38 MAPKs were silenced, pharmacologically blocked, or activated with NGF. Several findings suggesting that MAPKs control NCX emerged: (1) A decrease in NCX1 and NCX3 basal expression occurred when JNK or MEK1, the ERK1/2 upstream activator, were pharmacologically blocked, respectively; (2) NGF increased CREB1 and Sp1 binding to ncx1 promoter and in 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. NCX1 up-regulation was abolished upon either CREB1 or Sp1 silencing, whereas NCX2 down-regulation was abrogated only by CREB1 silencing. 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.