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Enhancement of acid-sensing ion channel activity by metabotropic P2Y UTP receptors in primary sensory neurons

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Abstract

Peripheral purinergic signaling plays an important role in nociception. Increasing evidence suggests that metabotropic P2Y receptors are also involved, but little is known about the underlying mechanism. Herein, we report that selective P2Y receptor agonist uridine 5′-triphosphate (UTP) can exert an enhancing effect on the functional activity of acid-sensing ion channels (ASICs), key sensors for extracellular protons, in rat dorsal root ganglia (DRG) neurons. First, UTP dose-dependently increased the amplitude of ASIC currents. UTP also shifted the concentration–response curve for proton upwards, with a 56.6 ± 6.4 % increase of the maximal current response to proton. Second, UTP potentiation of proton-gated currents can be mimicked by adenosine 5′-triphosphate (ATP), but not by P2Y1 receptor agonist ADP. Potentiation of UTP was blocked by P2Y receptor antagonist suramin and by inhibition of intracellular G protein, phospholipase C (PLC), protein kinase C (PKC), or protein interacting with C-kinase 1 (PICK1) signaling. Third, UTP altered acidosis-evoked membrane excitability of DRG neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acid stimuli. Finally, UTP dose-dependently exacerbated nociceptive responses to injection of acetic acid in rats. These results suggest that UTP enhanced ASIC-mediated currents and nociceptive responses, which reveal a novel peripheral mechanism underlying UTP-sensitive P2Y2 receptor involvement in hyperalgesia by sensitizing ASICs in primary sensory neurons.

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Abbreviations

ASIC:

Acid-sensing ion channels

ATP:

Adenosine 5′-triphosphate

DRG:

Dorsal root ganglion

IpH :

Proton-gated current

PICK1:

Protein interacting with C-kinase 1

PKC:

Protein kinase C

PLC:

Phospholipase C

TRPV1:

Transient receptor potential vanilloid receptor-1

UTP:

Uridine 5′-triphosphate

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (Nos. 31471062 and 81171039) and the Natural Science Foundation of Hubei Province of China (No. 2015CFA145).

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Authors and Affiliations

  1. Institute of Ion Channels, Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning, 437100, Hubei, People’s Republic of China

    Cuixia Ren, Xiong Gan, Jing Wu, Chun-Yu Qiu & Wang-Ping Hu

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  1. Cuixia Ren
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Correspondence to Wang-Ping Hu.

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Ren, C., Gan, X., Wu, J. et al. Enhancement of acid-sensing ion channel activity by metabotropic P2Y UTP receptors in primary sensory neurons. Purinergic Signalling 12, 69–78 (2016). https://doi.org/10.1007/s11302-015-9479-y

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