title: Small organic molecule disruptors of Cav3.2 - USP5 interactions reverse inflammatory and neuropathic pain.
abstract: BACKGROUND
  Cav3.2 channels facilitate nociceptive transmission and are upregulated in DRG neurons in response to nerve injury or peripheral inflammation. We reported that this enhancement of Cav3.2 currents in afferent neurons is mediated by deubiquitination of the channels by the deubiquitinase USP5, and that disrupting USP5/Cav3.2 channel interactions protected from inflammatory and neuropathic pain.
  
  
  RESULTS
  Here we describe the development of a small molecule screening assay for USP5-Cav3.2 disruptors, and report on two hits of a ~5000 compound screen - suramin and the flavonoid gossypetin. In mouse models of inflammatory pain and neuropathic pain, both suramin and gossypetin produced dose-dependent and long-lasting mechanical anti-hyperalgesia that was abolished or greatly attenuated in Cav3.2 null mice. Suramin and Cav3.2/USP5 Tat-disruptor peptides were also tested in models of diabetic neuropathy and visceral pain, and provided remarkable protection.
  
  
  CONCLUSIONS
  Overall, our findings provide proof of concept for a new class of analgesics that target T-type channel deubiquitination.
authors.affiliation: Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive, NW, Calgary, T2N 4N1, Canada. vgadotti@ucalgary.ca.
authors.forename: Vinicius M
authors.initials: VM
authors.lastname: Gadotti
authors.affiliation: Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive, NW, Calgary, T2N 4N1, Canada. agarcia@ucalgary.ca.
authors.forename: Agustin Garcia
authors.initials: AG
authors.lastname: Caballero
authors.affiliation: Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive, NW, Calgary, T2N 4N1, Canada. ndberger@ucalgary.ca.
authors.forename: N Daniel
authors.initials: ND
authors.lastname: Berger
authors.affiliation: Centre for Drug Research and Development, 2405 Wesbrook Mall - 4th Floor, Vancouver, BC, V6T 1Z3, Canada. clare_gladding@yahoo.co.uk.
authors.forename: Clare M
authors.initials: CM
authors.lastname: Gladding
authors.affiliation: Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive, NW, Calgary, T2N 4N1, Canada. linchen@ucalgary.ca.
authors.forename: Lina
authors.initials: L
authors.lastname: Chen
authors.affiliation: Centre for Drug Research and Development, 2405 Wesbrook Mall - 4th Floor, Vancouver, BC, V6T 1Z3, Canada. tpfeifer@cdrd.ca.
authors.forename: Tom A
authors.initials: TA
authors.lastname: Pfeifer
authors.affiliation: Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive, NW, Calgary, T2N 4N1, Canada. zamponi@ucalgary.ca.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Zamponi
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000503:physiopathology; D006801:Humans; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009437:Neuralgia / Q000378:metabolism* / Q000503:physiopathology; D009475:Neurons, Afferent / Q000378:metabolism*; D013498:Suramin / Q000494:pharmacology*; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism*
chemical_list: D000700:Analgesics; C504883:Cacna1h protein, mouse; D020747:Calcium Channels, T-Type; D013498:Suramin; D064570:Ubiquitin-Specific Proteases; C000604994:Usp5 protein, mouse