The Deubiquitinating Enzyme USP5 Modulates Neuropathic and Inflammatory Pain by Enhancing Cav3.2 Channel Activity
| العنوان: | The Deubiquitinating Enzyme USP5 Modulates Neuropathic and Inflammatory Pain by Enhancing Cav3.2 Channel Activity |
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| المؤلفون: | Vinicius M. Gadotti, Amaury François, Victoria Hodgkinson, Jawed Hamid, Mickael Deage, Norbert Weiss, Chris Bladen, Ivana A. Souza, Lina Chen, Gerald W. Zamponi, Patrick L. Stemkowski, Emmanuel Bourinet, Anne Pizzoccaro, Agustin Garcia-Caballero |
| المساهمون: | Department of Physiology and Pharmacology, University of Calgary-Hotchkiss Brain Institute, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS) |
| المصدر: | Neuron Neuron, Elsevier, 2014, 83 (5), pp.1144--58. ⟨10.1016/j.neuron.2014.07.036⟩ |
| بيانات النشر: | Elsevier BV, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Male, Inflammation/chemically induced/*physiopathology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Freund's Adjuvant, Nerve Tissue Proteins/metabolism, Pain Threshold/drug effects/physiology, Inbred C57BL, Transgenic, Membrane Potentials, Endopeptidases/genetics/*metabolism, Deubiquitinating enzyme, Small hairpin RNA, Calcium Channels, T-Type, Mice, 0302 clinical medicine, Ubiquitination/genetics/physiology, Ubiquitin, Cells, Cultured, Spinal Cord/cytology, 0303 health sciences, Gene knockdown, Cultured, biology, Voltage-dependent calcium channel, General Neuroscience, Neuralgia/drug therapy/*enzymology, Transfection, Ubiquitin ligase, Cell biology, Spinal Cord, Biochemistry, Hyperalgesia, T-Type/genetics/*metabolism, Pain Threshold, Sensory Receptor Cells, Neuroscience(all), Cells, Membrane Potentials/drug effects/genetics, Mice, Transgenic, Nerve Tissue Proteins, In Vitro Techniques, 03 medical and health sciences, Enzyme activator, Freund's Adjuvant/toxicity, Endopeptidases, Animals, Humans, Hyperalgesia/diagnosis/physiopathology, 030304 developmental biology, Inflammation, Animal, Ubiquitination, Sensory Receptor Cells/drug effects/physiology, Peptides/therapeutic use, Mice, Inbred C57BL, Disease Models, Animal, Disease Models, biology.protein, Neuralgia, Calcium Channels, Peptides, 030217 neurology & neurosurgery |
| الوصف: | International audience; T-type calcium channels are essential contributors to the transmission of nociceptive signals in the primary afferent pain pathway. Here, we show that T-type calcium channels are ubiquitinated by WWP1, a plasma-membrane-associated ubiquitin ligase that binds to the intracellular domain III-IV linker region of the Cav3.2 T-type channel and modifies specific lysine residues in this region. A proteomic screen identified the deubiquitinating enzyme USP5 as a Cav3.2 III-IV linker interacting partner. Knockdown of USP5 via shRNA increases Cav3.2 ubiquitination, decreases Cav3.2 protein levels, and reduces Cav3.2 whole-cell currents. In vivo knockdown of USP5 or uncoupling USP5 from native Cav3.2 channels via intrathecal delivery of Tat peptides mediates analgesia in both inflammatory and neuropathic mouse models of mechanical hypersensitivity. Altogether, our experiments reveal a cell signaling pathway that regulates T-type channel activity and their role in nociceptive signaling. |
| تدمد: | 0896-6273 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4a306311d005f4208709061cb39c28d9Test https://doi.org/10.1016/j.neuron.2014.07.036Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....4a306311d005f4208709061cb39c28d9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 08966273 |
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