Extracellular ATP activates transcription factor NFAT in mouse microglial cells

Abstract

AbstractThe effect of extracellular ATP on the activation of NFAT, an important transcription factor involved in cytokine expression, was investigated in the mouse microglial cell line N9. Incubation with ATP resulted in the potent and rapid activation of NFAT. Both NFAT1 and NFAT2 were activated by a calcineurin‐dependent pathway that required the influx of extracellular Ca2+. Inhibition of calcineurin by immunosuppressive drugs or Ca2+ chelation prevented ATP‐induced activation and nuclear translocation of NFAT. Activation of NFAT by ATP involved a P2X7 purinoreceptor‐mediated pathway. 2′,3′ ‐(4‐benzoyl)‐benzoyl‐ATP, an ATP analog with high affinity to the P2X7 receptor, was a strong agonist of NFAT activation. In addition, microglial N9 clones selected for the absence of P2X7, but still expressing the P2Y subtype, revealed no NFAT activation in response to ATP, although NFAT could be still triggered by agents increasing intracellular Ca2+. Our data therefore suggest that triggering of the P2X7 receptor by extracellular ATP is a potent mediator of transcription factor NFAT activation, and thus could be involved in early proinflammatory processes in the immune and nervous system. Drug Dev. Res. 52:213–219, 2001. © 2001 Wiley‐Liss, Inc.