EXTRACELLULAR ATP ACTIVATES TRANSCRIPTION FACTOR NF-KAPPA-B THROUGH THE P2Z PURINORECEPTOR BY SELECTIVELY TARGETING NF-KAPPA-B P65 (RELA)

Cells of the macrophage lineage express a peculiar surface receptor fo r extracellular ATP, designated P2Z/P2X(7) purinergic receptor, that i nduces pore formation and collapse of the plasma membrane potential, A lthough the function of the P2Z receptor is largely unknown, accumulat ing evidence implicates its role in cell signaling and immune reaction s. Here, we investigated the effect of P2Z receptor ligation on the ac tivation of NF-kappa B, a transcription factor controlling cytokine ex pression and apoptosis. Exposure of microglial cells to ATP but not ot her nucleotides resulted in potent NF-kappa B activation. This effect was specifically mediated by the P2Z receptor, because selective recep tor antagonists prevented NF-kappa B activation, NF-kappa B activation required reactive oxygen intermediates and proteases of the caspase f amily, because it was abolished by antioxidants and specific protease inhibitors. The subunit composition of the ATP-induced NF-kappa B-DNA complex was rather unusual, Whereas exposure to LPS-induced prototypic al NF-kappa B p50 homo and p65 (RelA)/p50 heterodimers, ATP stimulatio n resulted in the sole appearance of a p65 homodimer. This is the firs t demonstration that a certain stimulus activates a particular NF-kapp a B subunit. Because different NF-kappa B complexes exhibit distinct t ranscriptional and DNA-binding activities, ATP may control the express ion of a subset of NF-kappa B target genes distinct from those activat ed by classical proinflammatory mediators.