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The Journal of Neuroscience, April 5, 2006, 26(14):3798-3804; doi:10.1523/JNEUROSCI.5338-05.2006

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Cellular/Molecular
Inhibition of Apoptosis by P2Y₂ Receptor Activation: Novel Pathways for Neuronal Survival

David B. Arthur, Sean Georgi, Katerina Akassoglou, and Paul A. Insel

Department of Pharmacology, University of California, San Diego, La Jolla, California 92093

Correspondence should be addressed to Paul A. Insel, Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, 0636, La Jolla, CA 92037. Email: pinsel{at}ucsd.edu

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 ATPS, 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, ATPS 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.

Key words: dorsal root ganglion (DRG); nucleotide; ATP; purinergic; P2Y; Akt; Src; PC12; NGF

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Received Dec. 14, 2005; revised Feb. 27, 2006; accepted Feb. 27, 2006.

Correspondence should be addressed to Paul A. Insel, Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, 0636, La Jolla, CA 92037. Email: pinsel{at}ucsd.edu

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