D. Ferrari et al., P2X(7)/P2Z purinoreceptor-mediated activation of transcription factor NFATin microglial cells, J BIOL CHEM, 274(19), 1999, pp. 13205-13210
ATP is released from neurons and other cell types during several physiologi
cal and stress conditions under which it exerts various biological effects
upon binding to purinoreceptors, A rather peculiar purinoreceptor called P2
X(7)/P2Z is expressed on microglial and other myeloic cells. Although incre
asing evidence implicates an important role for P2Z in inflammatory process
es, little information exists about underlying signaling pathways. Here, we
report that in N9 microglial cells, extracellular ATP potently activates n
uclear factor of activated T cells (NFAT), a central transcription factor i
nvolved in cytokine gene expression. ATP activated NFAT rapidly (within 1 m
in), whereas activation of nuclear factor kappa B was much delayed, with st
rikingly distinct kinetics, During ATP stimulation, both NFAT-1 and NFAT-2
were activated by a calcineurin dependent pathway that required the influx
of extracellular calcium ions. Based on the pharmacological profile, NFAT a
ctivation was specifically mediated by P2Z and not by other purinoreceptors
. Ne cells that lacked P2Z but still expressed P2Y purinoreceptors failed t
o respond to NFAT activation. We conclude that P2Z-mediated NFAT activation
may represent a novel mechanism by which extracellular ATP can modulate ea
rly inflammatory gene expression within the nervous and immune system.