The deubiquitinating enzyme USP5 modulates neuropathic and inflammatory pain by enhancing Cav3.2 channel activity.

Abstract

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.

• Authors: Agustin García-Caballero, Vinicius M Gadotti, Patrick Stemkowski, Norbert Weiss, Ivana A Souza, Victoria Hodgkinson, Chris Bladen, Lina Chen, Jawed Hamid, Anne Pizzoccaro, Mickael Deage, Amaury François, Emmanuel Bourinet, Gerald W Zamponi
• Journal: Neuron (Neuron) Vol. 83 Issue 5 Pg. 1144-58 (Sep 03 2014) ISSN: 1097-4199 [Electronic] United States
• PMID: 25189210 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Cacna1h protein, mouse
• Calcium Channels, T-Type
• Nerve Tissue Proteins
• Peptides
• Freund's Adjuvant
• Endopeptidases
• ubiquitin isopeptidase

Topics

• Animals
• Calcium Channels, T-Type (genetics, metabolism)
• Cells, Cultured
• Disease Models, Animal
• Endopeptidases (genetics, metabolism)
• Freund's Adjuvant (toxicity)
• Humans
• Hyperalgesia (diagnosis, physiopathology)
• In Vitro Techniques
• Inflammation (chemically induced, physiopathology)
• Male
• Membrane Potentials (drug effects, genetics)
• Mice, Inbred C57BL
• Mice, Transgenic
• Nerve Tissue Proteins (metabolism)
• Neuralgia (drug therapy, enzymology)
• Pain Threshold (drug effects, physiology)
• Peptides (therapeutic use)
• Sensory Receptor Cells (drug effects, physiology)
• Spinal Cord (cytology)
• Transfection
• Ubiquitination (genetics, physiology)