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 P2Y2 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 ATPgammaS, 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, ATPgammaS 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/P2Y2 receptors and neurotrophin/TrkA--to sustain neuronal survival.
Arthur
David B
DB
Department of Pharmacology, University of California, San Diego, La Jolla, California 92093, USA.
Georgi
Sean
S
Akassoglou
Katerina
K
Insel
Paul A
PA
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002470:Cell Survival; D009414:Nerve Growth Factors / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D009711:Nucleotides / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058473:Receptors, Purinergic P2Y2; D015398:Signal Transduction
D009414:Nerve Growth Factors; D009711:Nucleotides; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; D020917:Receptor, trkA