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

Rakesh Kumar, Adina Hazan, Matan Geron, Rebbeca Steinberg, Lital Livni, Henry Matzner, Avi Priel

Research output: Contribution to journalArticlepeer-review

Abstract

Peripheral neuronal activation by inflammatorymediators is amultifaceted physiological response that involves a multitude of regulated cellular functions. One key pathway that has been shown to be involved in inflammatory pain isGq/GPCR,whose activation by inflammatorymediators 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 fromthe 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 showthat onlywhen 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.

Original languageAmerican English
Pages (from-to)1238-1247
Number of pages10
JournalFASEB Journal
Volume31
Issue number3
DOIs
StatePublished - Mar 2017

Keywords

  • Eicosanoids
  • Endovanilloids
  • Gq-GPCR
  • Inflammatory pain
  • TRP channels

All Science Journal Classification (ASJC) codes

  • Genetics
  • Molecular Biology
  • Biochemistry
  • Biotechnology

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