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

	author = {Lei Wu and Ting-ting Liu and Ying Jin and Shuang Wei and Chun-yu Qiu and Wang-ping Hu},
	title = {Endothelin-1 enhances acid-sensing ion channel currents in rat primary sensory neurons},
	journal = {Acta Pharmacologica Sinica},
	volume = {41},
	number = {8},
	year = {2020},
	keywords = {},
	abstract = {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.},
	issn = {1745-7254},	url = {}