Targeting the Transient Receptor Potential Vanilloid Type 1 (TRPV1) Assembly Domain Attenuates Inflammation-induced Hypersensitivity

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2014 May 9

PMID 24808184

Citations 19

Authors

Robyn Flynn

Kevin Chapman

Mircea Iftinca

Reem Aboushousha

Diego Varela

Christophe Altier

Affiliations

Soon will be listed here.

Abstract

The transient receptor potential channel vanilloid type 1 (TRPV1) is a non-selective cation channel expressed in sensory neurons of the dorsal root and trigeminal ganglia. TRPV1 is a polymodal channel activated by noxious heat, capsaicin, and protons. As a sensor for noxious stimuli, TRPV1 channel has been described as a key contributor to pain signaling. To form a functional channel, TRPV1 subunits must assemble into tetramers, and several studies have identified the TRPV1 C terminus as an essential element in subunit association. Here we combined biochemical assays with electrophysiology and imaging-based bimolecular fluorescence complementation (BiFC) and bioluminescence resonance energy transfer (BRET) in live cells to identify a short motif in the C-terminal tail of the TRPV1 subunit that governs channel assembly. Removing this region through early truncation or targeted deletion results in loss of subunit association and channel function. Importantly, we found that interfering with TRPV1 subunit association using a plasma membrane-tethered peptide attenuated mechanical and thermal hypersensitivity in two mouse models of inflammatory hyperalgesia. This represents a novel mechanism to disrupt TRPV1 subunit assembly and hence may offer a new analgesic tool for pain relief.

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References

Zygmunt P, Petersson J, Andersson D, Chuang H, Sorgard M, Di Marzo V . Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature. 1999; 400(6743):452-7. DOI: 10.1038/22761. View

Moran M, McAlexander M, Biro T, Szallasi A . Transient receptor potential channels as therapeutic targets. Nat Rev Drug Discov. 2011; 10(8):601-20. DOI: 10.1038/nrd3456. View

Basbaum A, Bautista D, Scherrer G, Julius D . Cellular and molecular mechanisms of pain. Cell. 2009; 139(2):267-84. PMC: 2852643. DOI: 10.1016/j.cell.2009.09.028. View

Heroux M, Hogue M, Lemieux S, Bouvier M . Functional calcitonin gene-related peptide receptors are formed by the asymmetric assembly of a calcitonin receptor-like receptor homo-oligomer and a monomer of receptor activity-modifying protein-1. J Biol Chem. 2007; 282(43):31610-20. DOI: 10.1074/jbc.M701790200. View

Liao M, Cao E, Julius D, Cheng Y . Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature. 2013; 504(7478):107-12. PMC: 4078027. DOI: 10.1038/nature12822. View

Covic L, Gresser A, Talavera J, Swift S, Kuliopulos A . Activation and inhibition of G protein-coupled receptors by cell-penetrating membrane-tethered peptides. Proc Natl Acad Sci U S A. 2002; 99(2):643-8. PMC: 117359. DOI: 10.1073/pnas.022460899. View

De-la-Rosa V, Rangel-Yescas G, Ladron-de-Guevara E, Rosenbaum T, Islas L . Coarse architecture of the transient receptor potential vanilloid 1 (TRPV1) ion channel determined by fluorescence resonance energy transfer. J Biol Chem. 2013; 288(41):29506-17. PMC: 3795249. DOI: 10.1074/jbc.M113.479618. View

Jeske N, Patwardhan A, Ruparel N, Akopian A, Shapiro M, Henry M . A-kinase anchoring protein 150 controls protein kinase C-mediated phosphorylation and sensitization of TRPV1. Pain. 2009; 146(3):301-307. PMC: 2783249. DOI: 10.1016/j.pain.2009.08.002. View

Bohlen C, Priel A, Zhou S, King D, Siemens J, Julius D . A bivalent tarantula toxin activates the capsaicin receptor, TRPV1, by targeting the outer pore domain. Cell. 2010; 141(5):834-45. PMC: 2905675. DOI: 10.1016/j.cell.2010.03.052. View

10.

Ogbonna A, Clark A, Gentry C, Hobbs C, Malcangio M . Pain-like behaviour and spinal changes in the monosodium iodoacetate model of osteoarthritis in C57Bl/6 mice. Eur J Pain. 2012; 17(4):514-26. DOI: 10.1002/j.1532-2149.2012.00223.x. View

11.

Gavva N, Klionsky L, Qu Y, Shi L, Tamir R, Edenson S . Molecular determinants of vanilloid sensitivity in TRPV1. J Biol Chem. 2004; 279(19):20283-95. DOI: 10.1074/jbc.M312577200. View

12.

Cao E, Liao M, Cheng Y, Julius D . TRPV1 structures in distinct conformations reveal activation mechanisms. Nature. 2013; 504(7478):113-8. PMC: 4023639. DOI: 10.1038/nature12823. View

13.

Zhang X, Li L, McNaughton P . Proinflammatory mediators modulate the heat-activated ion channel TRPV1 via the scaffolding protein AKAP79/150. Neuron. 2008; 59(3):450-61. DOI: 10.1016/j.neuron.2008.05.015. View

14.

Storti B, Bizzarri R, Cardarelli F, Beltram F . Intact microtubules preserve transient receptor potential vanilloid 1 (TRPV1) functionality through receptor binding. J Biol Chem. 2012; 287(10):7803-11. PMC: 3293569. DOI: 10.1074/jbc.M111.332296. View

15.

Phillips E, Reeve A, Bevan S, McIntyre P . Identification of species-specific determinants of the action of the antagonist capsazepine and the agonist PPAHV on TRPV1. J Biol Chem. 2004; 279(17):17165-72. DOI: 10.1074/jbc.M313328200. View

16.

Schnizler K, Shutov L, Van Kanegan M, Merrill M, Nichols B, McKnight G . Protein kinase A anchoring via AKAP150 is essential for TRPV1 modulation by forskolin and prostaglandin E2 in mouse sensory neurons. J Neurosci. 2008; 28(19):4904-17. PMC: 2641040. DOI: 10.1523/JNEUROSCI.0233-08.2008. View

17.

Okun A, Liu P, Davis P, Ren J, Remeniuk B, Brion T . Afferent drive elicits ongoing pain in a model of advanced osteoarthritis. Pain. 2012; 153(4):924-933. PMC: 3313555. DOI: 10.1016/j.pain.2012.01.022. View

18.

Szallasi A, Blumberg P . [3H]resiniferatoxin binding by the vanilloid receptor: species-related differences, effects of temperature and sulfhydryl reagents. Naunyn Schmiedebergs Arch Pharmacol. 1993; 347(1):84-91. DOI: 10.1007/BF00168777. View

19.

Harvey V, Dickenson A . Behavioural and electrophysiological characterisation of experimentally induced osteoarthritis and neuropathy in C57Bl/6 mice. Mol Pain. 2009; 5:18. PMC: 2678995. DOI: 10.1186/1744-8069-5-18. View

20.

Jordt S, Julius D . Molecular basis for species-specific sensitivity to "hot" chili peppers. Cell. 2002; 108(3):421-30. DOI: 10.1016/s0092-8674(02)00637-2. View