Schematic depiction of the signal transduction events occurring in microglia following P2 receptor activation. Extracellular calcium influx triggered by activation of ionotropic P2 receptors leads to activation of calcineurin and dephosphorylation/activation of NFAT (nuclear factor of activated T cells). P2 receptor activation also results in activation of phospholipases and D (PL, PLD), as well as tyrosine phosphorylation (P-Tyr) and activation of mitogen-activated protein kinase (MAPK) pathway proteins (MAPK kinase, MEK; extracellular signal-regulated kinase, ERK). The latter can then influence the activity of transcription factors like NF-B (nuclear factor-B), CREB (cyclic AMP response element (CRE)-binding protein), and AP-1 (activator protein-1) which upregulate expression of pro-inflammatory genes, such as cyclooxgenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Activation of P2 receptors also leads to p38 MAPK activation with consequent phosphorylation/activation of CREB. Broken lines indicate multistep pathways.