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

• Published in: Acta pharmacologica Sinica Vol. 41; no. 8; pp. 1049 - 1057
• Main Authors: Wu, Lei, Liu, Ting-Ting, Jin, Ying, Wei, Shuang, Qiu, Chun-Yu, Hu, Wang-Ping
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.08.2020; Springer Singapore
• Subjects: Acidity; Acidosis; Amiloride; Capsaicin receptors; Dorsal root ganglia; Endothelin 1; Endothelin ETA receptors; Endothelin ETB receptors; Hyperalgesia; Ion channels; Kinases; Pain perception; Protein kinase C; Protons; Sensory neurons; Signal transduction; Sodium channels; Vasoactive agents; amiloride; nociceptive response; BQ-788; acid-sensing ion channels; dorsal root ganglion neuron; APETx2; endothelin-1; BQ-123
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-019-0348-z

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 EC 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 (ET R), but not endothelin-B receptor (ET R) in both DRG neurons and CHO cells co-expressing ASIC3 and ET R. 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 ET R and PKC signaling pathway, which may contribute to peripheral ET-1-induced nociceptive behavior in rats.