ETAR and protein kinase A pathway mediate ET-1 sensitization of TRPA1 channel: A molecular mechanism of ET-1-induced mechanical hyperalgesia.

Journal Article (Journal Article)

Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor that has been widely known as a pain mediator involved in various pain states. Evidence indicates that ET-1 sensitizes transient receptor potential cation channel, subfamily A, member 1 (TRPA1) in vivo. But the molecular mechanisms still remain unknown. We aim to explore whether ET-1 sensitizes TRPA1 in primary sensory neurons and the molecular mechanisms. Ca2+ imaging, immunostaining, electrophysiology, animal behavioral assay combined with pharmacological experiments were performed. ET-1 sensitized TRPA1-mediated Ca2+ responses in human embryonic kidney (HEK)293 cells as well as in cultured native mouse dorsal root ganglion (DRG) neurons. ET-1 also sensitized TRPA1 channel currents. ET-1 sensitized TRPA1 activated by endogenous agonist H2O2. ETA receptor (ETAR) colocalized with TRPA1 in DRG neurons. ET-1-induced TRPA1 sensitization in vivo was mediated via ETAR and protein kinase A (PKA) pathway in HEK293 cells and DRG neurons. Pharmacological blocking of ETAR, PKA, and TRPA1 significantly attenuated ET-1-induced mechanical hyperalgesia in mice. Our results suggest that TRPA1 acts as a molecular target for ET-1, and sensitization of TRPA1 through ETAR-PKA pathway contributes to ET-1-induced mechanical hyperalgesia. Pharmacological targeting of TRPA1 and ETAR-PKA pathway may provide effective strategies to alleviate pain conditions associated with ET-1.

Full Text

Duke Authors

Cited Authors

  • Zheng, X; Tai, Y; He, D; Liu, B; Wang, C; Shao, X; Jordt, S-E; Liu, B

Published Date

  • January 2019

Published In

Volume / Issue

  • 15 /

Start / End Page

  • 1744806919842473 -

PubMed ID

  • 30990108

Pubmed Central ID

  • PMC6537062

Electronic International Standard Serial Number (EISSN)

  • 1744-8069

Digital Object Identifier (DOI)

  • 10.1177/1744806919842473


  • eng

Conference Location

  • United States