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Nucleotides excite sensory neurons via two P2Y receptors and a dual signaling cascade

Background

Sensory neurons innervating the skin provide information about physical contact between organisms and the environment including stimuli that lead to pain sensation. Metabotropic P2Y receptors have been suggested to be important in the signaling of sensory neurons, but their effects and signaling mechanism remained controversial.

Methods

Patch-clamp recordings were performed in primary cultures of dorsal root ganglion (DRG) neurons from neonatal rats, P2Y receptor ligands and signaling interceptors were applied.

Results

ADP (EC50: 7.5 μM), ATP (EC50: 0.5 μM), UTP (EC50: 0.8 μM), and thio-UTP (EC50: 0.4 μM) increased the number of action potentials fired in response to current injection; UDP failed to affect action potential firing. The effect of ADP was attenuated by a P2Y1 antagonist. This enhancement of excitability was abolished by flupirtine (30 μM), a KV7 channel opener, and slightly, but insignificantly attenuated by iodoresiniferatoxin (0.3 μM). Under voltage clamp, the same nucleotides inhibited currents through KV7 channels in a concentration-dependent manner with similar EC50 values. The P2Y1-specific agonist MRS2365 also caused an inhibition of KV7 channels (EC50 value of 8.68 nM), and the P2Y1 antagonist MRS2179 attenuated the inhibition by ADP. Treatment of sensory neurons with the phospholipase C inhibitor U73122, with the Ca2+-ATPase inhibitor thapsigargin, or the Ca2+ chelator BAPTA-AM abolished the inhibition of KV7 channels by ADP. Moreover, ADP and ATP increased amplitudes of currents through TRPV1 receptors evoked by capsaicin.

Conclusion

Activation of P2Y1 and P2Y2 receptors increases the excitability of sensory neurons via a dual mechanism: an inhibition of KV7 channels via phospholipase C and increases in intracellular Ca2+, and a sensitization of TRPV1 receptors, with the former mechanism being the decisive one.

Acknowledgements

Supported by FWF.

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Correspondence to Stefan Boehm.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Yousuf, A., Boehm, S. Nucleotides excite sensory neurons via two P2Y receptors and a dual signaling cascade. BMC Pharmacol 9, A17 (2009). https://doi.org/10.1186/1471-2210-9-S2-A17

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Keywords

  • Dorsal Root Ganglion
  • Capsaicin
  • Sensory Neuron
  • Thapsigargin
  • Action Potential Firing