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The physiological role of the uracil nucleotide-preferring P2Y6 and P2Y4 receptors is still unclear, although they are widely distributed in various tissues. In an effort to identify their biological functions, we found that activation by UDP of the rat P2Y6 receptor expressed in 1321N1 human astrocytes significantly reduced cell death induced by tumor necrosis factor α (TNFα). This effect of UDP was not observed in non-transfected 1321N1 cells. Activation of the human P2Y4 receptor expressed in 1321N1 cells by UTP did not elicit this protective effect, although both receptors were coupled to phospholipase C. The activation of P2Y6 receptors prevented the activation of both caspase-3 and caspase-8 resulting from TNFα exposure. Even a brief (10-min) incubation with UDP protected the cells against TNFα-induced apoptosis. Interestingly, UDP did not protect the P2Y6-1321N1 cells from death induced by other methods, i.e. oxidative stress induced by hydrogen peroxide and chemical ischemia. Therefore, it is suggested that P2Y6 receptors interact rapidly with the TNFα-related intracellular signals to prevent apoptotic cell death. This is the first study to describe the cellular protective role of P2Y6 nucleotide receptor activation.