Signaling pathways activated by extracellular nucleotides through the P2Y(2) receptor: An in vitro ischemia model

Extracellular nucleotides through the P2Y2 receptor activate signal transduction that involve the activation of protein kinases such as the MAPK family and Akt/PKB and transcription factors regulating gene expression to induce cellular responses such as proliferation and survival. The amino acid sequence of the human P2Y2 receptor have indicated the presence of an arginine-glycine-aspartic acid (RGD) integrin binding motif that is localized at the first extracellular loop of this receptor. The P2Y2 receptor also posses a proline rich sequence at the intracellular region (C-terminal) which encompasses an SH3 binding domain that may regulate the signal transduction that induce the receptor. Receptors for adenosine and ATP are expressed in astrocytes. Larger amounts of nucleotides and nucleosides are released following brain trauma and ischemia, which can activate immediately P2 receptors such as P2Y2 receptors. Therefore, this study investigated the role and molecular mechanisms that extracellular nucleotides through the P2Y2 receptor activate during and after a cerebral ischemia episode and the molecular determinants (extracellular and intracellular domains) of the P2Y2 receptor by which extracellular nucleotides mediate astrocytic activation. The activation of MAPK and Akt/PKB is partially dependent of the interaction of the P2Y2 receptor with the alphavbeta 3 integrin through the RGD sequence and partially dependent of the proline rich sequence. The activation of these protein kinases during ischemia is mediated principally by the nucleotides released and the activation of P2Y 2 receptor but also by glutamate receptors. The activation of these protein kinases by P2Y2 receptor induces a survival signal during an episode of ischemia.