Activation of transient receptor potential vanilloid 1 by lipoxygenase metabolites depends on PKC phosphorylation

FASEB J. 2017 Mar;31(3):1238-1247. doi: 10.1096/fj.201601132R. Epub 2016 Dec 16.


Peripheral neuronal activation by inflammatory mediators is a multifaceted physiological response that involves a multitude of regulated cellular functions. One key pathway that has been shown to be involved in inflammatory pain is Gq/GPCR, whose activation by inflammatory mediators is followed by the regulated response of the cation channel transient receptor potential vanilloid 1 (TRPV1). However, the mechanism that underlies TRPV1 activation downstream of the Gq/GPCR pathway has yet to be fully defined. In this study, we employ pharmacological and molecular biology tools to dissect this activation mechanism via perforated-patch recordings and calcium imaging of both neurons and a heterologous system. We showed that TRPV1 activity downstream of Gq/GPCR activation only produced a subdued current, which was noticeably different from the robust current that is typical of TRPV1 activation by exogenous stimuli. Moreover, we specifically demonstrated that 2 pathways downstream of Gq/GPCR signaling, namely endovanilloid production by lipoxygenases and channel phosphorylation by PKC, converge on TRPV1 to evoke a tightly regulated response. Of importance, we show that only when both pathways are acting on TRPV1 is the inflammatory-mediated response achieved. We propose that the requirement of multiple signaling events allows subdued TRPV1 activation to evoke regulated neuronal response during inflammation.-Kumar R., Hazan, A., Geron, M., Steinberg, R., Livni, L., Matzner, H., Priel, A. Activation of transient receptor potential vanilloid 1 by lipoxygenase metabolites depends on PKC phosphorylation.

Keywords: Gq-GPCR; TRP channels; eicosanoids; endovanilloids; inflammatory pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • Cells, Cultured
  • Eicosanoids / pharmacology
  • GTP-Binding Protein alpha Subunits / metabolism
  • HEK293 Cells
  • Humans
  • Lipoxygenase / metabolism*
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / physiology
  • Phosphorylation
  • Protein Kinase C / metabolism*
  • Protein Processing, Post-Translational
  • Rats
  • TRPV Cation Channels / metabolism*


  • Eicosanoids
  • GTP-Binding Protein alpha Subunits
  • TRPV Cation Channels
  • Trpv1 protein, rat
  • Lipoxygenase
  • Protein Kinase C