Calcineurin controls the expression of isoform 4CII of the plasma membraneCa2+ pump in neurons

The expression of the CII splice variant of the plasma membrane Ca2+ ATPase 4 (PMCA4) was down-regulated in granule neurons when they were cultured un der conditions of partial membrane depolarization (25 mM KCl), which are re quired for long term in vitro survival of the neurons. These conditions, wh ich cause a chronic increase of the resting free Ca2+ concentration in the neurons, have recently been shown to promote up-regulation of the PMCA2, 3, and 1CII isoforms, Whereas the chronic, i.e. >3 days, Ca2+ increase was ne cessary for the up-regulation of the PMCA1CII, 2, and 3, the downregulation of the PMCA4CII mRNA was already evident 1-2 h after the start of culturin g in 25 mhz KCl, The immunosuppressant calcineurin inhibitor FK506 inhibite d the down-regulation of the PMCA4CII at both the protein and the mRNA leve l but did not affect the changes of the other PMCA pumps, Direct evidence f or the involvement of calcineurin in the down-regulation of the PMCA4CII wa s obtained by overexpressing a truncated, constitutively active, and Ca2+-i ndependent form of calcineurin; under these conditions, depolarization was not required for the down-regulation of the PMCA4CII pump. De novo synthesi s of (transcription) factors was required for the down-regulation of the PM CA4CII mRNA Calcineurin, therefore, controls the neuronal transcription of PMCA4CII, a splice variant of the pump isoforms that is found almost exclus ively in brain.