Inhibition of apoptosis by P2Y2 receptor activation:: Novel pathways for neuronal survival

Cell survival is an essential function in the development and maintenance of the nervous system. We demonstrate here a previously unappreciated role for extracellular nucleotide signaling through the P2Y(2) receptor in the survival of neurons: PC12 (pheochromocytoma 12) cells and dorsal root ganglion neurons are protected from serum starvation-induced apoptosis by ATP, UTP, and ATP gamma S, an effect mediated via P2Y2 receptors, as demonstrated by small interfering RNA and genetic knock-out models. This protection occurs independently of neurophin signaling but requires Src activation of ERK ( extracellular signal-regulated kinase) and Akt. Moreover, ATP gamma S and NGF act synergistically to enhance neuronal survival through enhanced TrkA signaling. The results, which define a novel mechanism for inhibition of apoptosis, implicate parallel, interacting systems-extracellular nucleotides/P2Y(2) receptors and neurotrophin/TrkA - to sustain neuronal survival.