Endothelin-1 enhances acid-sensing ion channel currents in rat primary sensory neurons

Lei Wu1,2, Ting-ting Liu1, Ying Jin1, Shuang Wei1, Chun-yu Qiu1,2, Wang-ping Hu1
1 Research Center of Basic Medical Sciences, School of Basic Medical Sciences, Hubei University of Science and Technology, Xianning 437100, China
2 Department of Pharmacology, Hubei University of Science and Technology, Xianning 437100, China
Correspondence to: Wang-ping Hu:,
DOI: 10.1038/s41401-019-0348-z
Received: 6 August 2019
Accepted: 12 December 2019
Advance online: 27 February 2020


Endothelin-1 (ET-1), an endogenous vasoactive peptide, has been found to play an important role in peripheral pain signaling. Acid- sensing ion channels (ASICs) are key sensors for extracellular protons and contribute to pain caused by tissue acidosis. It remains unclear whether an interaction exists between ET-1 and ASICs in primary sensory neurons. In this study, we reported that ET-1 enhanced the activity of ASICs in rat dorsal root ganglia (DRG) neurons. In whole-cell voltage-clamp recording, ASIC currents were evoked by brief local application of pH 6.0 external solution in the presence of TRPV1 channel blocker AMG9810. Pre-application with ET-1 (1−100 nM) dose-dependently increased the proton-evoked ASIC currents with an EC50 value of 7.42 ± 0.21 nM. Pre-application with ET-1 (30 nM) shifted the concentration–response curve of proton upwards with a maximal current response increase of 61.11% ± 4.33%. We showed that ET-1 enhanced ASIC currents through endothelin-A receptor (ETAR), but not endothelin-B receptor (ETBR) in both DRG neurons and CHO cells co-expressing ASIC3 and ETAR. ET-1 enhancement was inhibited by blockade of G-protein or protein kinase C signaling. In current-clamp recording, pre-application with ET-1 (30 nM) significantly increased acid-evoked firing in rat DRG neurons. Finally, we showed that pharmacological blockade of ASICs by amiloride or APETx2 significantly alleviated ET-1- induced flinching and mechanical hyperalgesia in rats. These results suggest that ET-1 sensitizes ASICs in primary sensory neurons via ETAR and PKC signaling pathway, which may contribute to peripheral ET-1-induced nociceptive behavior in rats.
Keywords: endothelin-1; acid-sensing ion channels; dorsal root ganglion neuron; nociceptive response; BQ-123; BQ-788; amiloride; APETx2

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