Co-activation of P2Y2 receptor and TRPV channel by ATP: implications for ATP induced pain

Cell Mol Neurobiol. 2005 Aug;25(5):819-32. doi: 10.1007/s10571-005-4936-8.


1. Extracellular ATP is recognized as a peripheral modulator of pain. Activation of ionotropic P2X receptors in sensory neurons has been implicated in induction of pain, whereas metabotropic P2Y receptors in potentiation of pain induced by chemical or physical stimuli via capsaicin sensitive TRPV1 channel. Here we report that P2Y2 receptor activation by ATP can activate the TRPV1 channel in absence of any other stimuli. 2. ATP-induced Ca2+ signaling was studied in Neuro2a cells. ATP evoked release of intracellular Ca2+ from ER and Ca2+ influx through a fast inactivating channel. The Ca2+ response was induced by P2Y receptor agonists in the order of potency ATP>or=UTP>or=ATPgammaS>ADP and was inhibited by suramin and PPADS. The P2X receptor agonist alpha beta methyl ATP was ineffective. 3. The Ca2+ influx was blocked by ruthenium red, an inhibitor of TRPV1 channel. Capsaicin, the most potent activator of the TRPV1 channel, evoked a fast inactivating Ca2+ transient suggesting the presence of endogenous TRPV1 channels in Neuro2a cells. NMS and PDBu, repressors of IP3 formation, drastically inhibited both the components of Ca2+ response. 4. Our data show co-activation of the P2Y2 receptor and capsaicin sensitive TRPV1 channel by ATP. Such functional interaction between endogenous P2Y2 receptor and TRPV1 channels could explain the ATP-induced pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / pharmacology*
  • Animals
  • Calcium / metabolism
  • Capsaicin / pharmacology
  • Cell Line
  • Dose-Response Relationship, Drug
  • Hyperalgesia / metabolism
  • Ion Channels / metabolism*
  • Mice
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Pain / metabolism*
  • Receptors, Purinergic P2 / metabolism*
  • Receptors, Purinergic P2Y2
  • TRPV Cation Channels


  • Ion Channels
  • P2ry2 protein, mouse
  • Receptors, Purinergic P2
  • Receptors, Purinergic P2Y2
  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • Adenosine Triphosphate
  • Capsaicin
  • Calcium