title: TRPV1 Nociceptor Activity Initiates USP5/T-type Channel-Mediated Plasticity.
abstract: Peripheral nerve injury and tissue inflammation result in upregulation of the deubiquitinase USP5, thus causing a dysregulation of T-type calcium channel activity and increased pain sensitivity. Here, we have explored the role of afferent fiber activity in this process. Conditioning stimulation of optogenetically targeted cutaneous TRPV1 expressing nociceptors, but not that of non-nociceptive fibers, resulted in enhanced expression of USP5 in mouse dorsal root ganglia and spinal dorsal horn, along with decreased withdrawal thresholds for thermal and mechanical stimuli that abated after 24 hr. This sensitization was drastically reduced by an interfering peptide that prevented USP5-Cav3.2 association. Sensitization was relieved by pharmacological block of TRPV1 afferents, but not of myelinated neurons. In spinal cord slice recordings, we could optogenetically trigger an activity-dependent potentiation of presynaptic neurotransmission in the spinal dorsal horn that relied on Cav3.2 channel activity. This neuronal-activity-induced USP5 upregulation may underlie a protective, transient sensitization of the pain pathway.
authors.affiliation: Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Stemkowski
authors.affiliation: Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Agustin
authors.initials: A
authors.lastname: García-Caballero
authors.affiliation: Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Vinicius De Maria
authors.initials: VM
authors.lastname: Gadotti
authors.affiliation: Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Said
authors.initials: S
authors.lastname: M'Dahoma
authors.affiliation: Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Shuo
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Stefanie Alice Gertrud
authors.initials: SAG
authors.lastname: Black
authors.affiliation: Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Lina
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Ivana Assis
authors.initials: IA
authors.lastname: Souza
authors.affiliation: Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada. Electronic address: zamponi@ucalgary.ca.
authors.forename: Gerald Werner
authors.initials: GW
authors.lastname: Zamponi
mesh_terms: D000818:Animals; D020747:Calcium Channels, T-Type / Q000235:genetics* / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism / Q000503:physiopathology; D006930:Hyperalgesia / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D009413:Nerve Fibers, Myelinated / Q000473:pathology; D009437:Neuralgia / Q000378:metabolism / Q000473:pathology; D009475:Neurons, Afferent / Q000378:metabolism / Q000473:pathology; D010146:Pain / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009435:Synaptic Transmission / Q000235:genetics; D050916:TRPV Cation Channels / Q000235:genetics* / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases / Q000235:genetics* / Q000378:metabolism
chemical_list: C504883:Cacna1h protein, mouse; D020747:Calcium Channels, T-Type; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D064570:Ubiquitin-Specific Proteases; C000604994:Usp5 protein, mouse
keywords: Cav3.2; DRG; T-type; TRPV1; USP5; optogenetics; pain; spinal cord