title: Activation of transient receptor potential vanilloid 1 by lipoxygenase metabolites depends on PKC phosphorylation.
abstract: 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 mechanismviaperforated-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.
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Adina
authors.initials: A
authors.lastname: Hazan
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Matan
authors.initials: M
authors.lastname: Geron
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Rebbeca
authors.initials: R
authors.lastname: Steinberg
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Lital
authors.initials: L
authors.lastname: Livni
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Henry
authors.initials: H
authors.lastname: Matzner
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel avip@ekmd.huji.ac.il.
authors.forename: Avi
authors.initials: A
authors.lastname: Priel
mesh_terms: D000200:Action Potentials; D000818:Animals; D002478:Cells, Cultured; D015777:Eicosanoids / Q000494:pharmacology; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008084:Lipoxygenase / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D051381:Rats; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D015777:Eicosanoids; D044385:GTP-Binding Protein alpha Subunits; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D008084:Lipoxygenase; D011493:Protein Kinase C
keywords: Gq-GPCR; TRP channels; eicosanoids; endovanilloids; inflammatory pain