Small organic molecule disruptors of Cav3.2 - USP5 interactions reverse inflammatory and neuropathic pain

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...

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Bibliographic Details
Published in:Molecular pain 2015-03, Vol.11, p.12
Main Authors: Gadotti, Vinicius M, Caballero, Agustin Garcia, Berger, N Daniel, Gladding, Clare M, Chen, Lina, Pfeifer, Tom A, Zamponi, Gerald W
Format: Article
Language:English
Subjects:
Analgesics - pharmacology
Animals
Calcium Channels, T-Type - metabolism
Ganglia, Spinal - physiopathology
Humans
Hyperalgesia - metabolism
Hyperalgesia - physiopathology
Inflammation - metabolism
Mice
Mice, Knockout
Neuralgia - metabolism
Neuralgia - physiopathology
Neurons, Afferent - metabolism
Suramin - pharmacology
Ubiquitin-Specific Proteases - metabolism
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Summary: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. 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. Overall, our findings provide proof of concept for a new class of analgesics that target T-type channel deubiquitination.
ISSN:1744-8069
DOI:10.1186/s12990-015-0011-8