title: TNFα induces co-trafficking of TRPV1/TRPA1 in VAMP1-containing vesicles to the plasmalemma via Munc18-1/syntaxin1/SNAP-25 mediated fusion.
abstract: Transient receptor potential (TRP) A1 and V1 channels relay sensory signals, yet little is known about their transport to the plasmalemma during inflammation. Herein, TRPA1 and TRPV1 were found on vesicles containing calcitonin gene-related peptide (CGRP), accumulated at sites of exo- and endo-cytosis, and co-localised on fibres and cell bodies of cultured sensory neurons expressing both. A proinflammatory cytokine, TNFα, elevated their surface content, and both resided in close proximity, indicating co-trafficking. Syntaxin 1-interacting protein, Munc18-1, proved necessary for the response to TNFα, and for TRPV1-triggered CGRP release. TNFα-induced surface trafficking of TRPV1 and TRPA1 required a synaptic vesicle membrane protein VAMP1 (but not 2/3), which is essential for CGRP exocytosis from large dense-core vesicles. Inactivation of two proteins on the presynaptic plasma membrane, syntaxin-1 or SNAP-25, by botulinum neurotoxin (BoNT)/C1 or /A inhibited the TNFα-elevated delivery. Accordingly, enhancement by TNFα of Ca(2+) influx through the upregulated surface-expressed TRPV1 and TRPA1 channels was abolished by BoNT/A. Thus, in addition, the neurotoxins' known inhibition of the release of pain transmitters, their therapeutic potential is augmented by lowering the exocytotic delivery of transducing channels and the resultant hyper-sensitisation in inflammation.
authors.affiliation: International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland.|Department of Dermatology and Charles Institute for Translational Dermatology, University College Dublin, Ireland.
authors.forename: Jianghui
authors.initials: J
authors.lastname: Meng
authors.affiliation: International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland.
authors.forename: Jiafu
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Dermatology and Charles Institute for Translational Dermatology, University College Dublin, Ireland.
authors.forename: Martin
authors.initials: M
authors.lastname: Steinhoff
authors.affiliation: International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland.
authors.forename: James Oliver
authors.initials: JO
authors.lastname: Dolly
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D006801:Humans; D008561:Membrane Fusion / Q000502:physiology; D051938:Munc18 Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000166:cytology / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000235:genetics / Q000378:metabolism*; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism*; D050827:Syntaxin 1 / Q000235:genetics / Q000378:metabolism*; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D050987:Vesicle-Associated Membrane Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051938:Munc18 Proteins; C494210:Snap25 protein, rat; C497939:Stxbp1 protein, rat; D050825:Synaptosomal-Associated Protein 25; D050827:Syntaxin 1; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050916:TRPV Cation Channels; C480976:Trpa1 protein, rat; C493922:Trpv1 protein, rat; D014409:Tumor Necrosis Factor-alpha; D050987:Vesicle-Associated Membrane Protein 1; C494705:vesicle-associated membrane protein 1, rat