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

J Neurosci. 2006 Apr 5;26(14):3798-804. doi: 10.1523/JNEUROSCI.5338-05.2006.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Cell Survival
  • Nerve Growth Factors / metabolism*
  • Neurons / cytology*
  • Neurons / metabolism*
  • Nucleotides / metabolism*
  • PC12 Cells
  • Rats
  • Receptor, trkA / metabolism*
  • Receptors, Purinergic P2 / metabolism*
  • Receptors, Purinergic P2Y2
  • Signal Transduction*

Substances

  • Nerve Growth Factors
  • Nucleotides
  • Receptors, Purinergic P2
  • Receptors, Purinergic P2Y2
  • Receptor, trkA