Fig. 6. Model of nucleotide signaling in sensory neurons.

1) In response to a painful stimulus to the skin (or other peripheral tissue), ATP is released to activate ionotropic and metabotropic ATP receptors. 2) ATP signaling is terminated by degradation of ATP to ADP by NTPDase3, resulting in a more prolonged activation of ADP receptors (due to the lower efficiency of NTPDase3 for ADP hydrolysis over ATP), as well as inhibition by ADP of adenosine production by 5′-ectonucleotidases. Whereas ATP receptors (P2X, P2Y₂, P2Y₄) are either ionotropic or Gq-coupled and thus likely to be excitatory, ADP receptors in sensory neurons include both the pro-nociceptive Gq-coupled P2Y₁ and the Gi-coupled P2Y₁₂ and P2Y₁₃ receptors, which are likely to exert an anti-nociceptive influence (Malin and Molliver, 2010). 3) Finally, hydrolysis of ADP provides a pool of extracellular AMP and removes inhibition of 5′-ectonucleotidases, resulting in production of adenosine (ADO) by NT5E and TM-PAP (PAP). Arrow sizes indicate differences in efficiency for hydrolysis of ATP versus ADP and AMP. The G protein coupling of each receptor is indicated. Zylka and colleagues have demonstrated a powerful antinociceptive effect of adenosine in the dorsal horn mediated by the A₁ receptor (Zylka et al. 2008, Sowa et al., 2009, Sowa et al., 2010). This figure illustrates the signaling machinery for nucleotide signaling at the peripheral sensory axon terminal, however a similar organization is likely at the central presynaptic terminal in the dorsal horn. Note that NTPDase3 expression was also found in the superficial epidermis (not shown), and presumably regulates levels of ATP released in this region. This figure was constructed in part using the pathway builder tool on www.proteinlounge.com.