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.

journal_name

Neuron

journal_title

Neuron

authors

García-Caballero A,Gadotti VM,Stemkowski P,Weiss N,Souza IA,Hodgkinson V,Bladen C,Chen L,Hamid J,Pizzoccaro A,Deage M,François A,Bourinet E,Zamponi GW

doi

10.1016/j.neuron.2014.07.036

subject

Has Abstract

pub_date

2014-09-03 00:00:00

pages

1144-58

issue

5

eissn

0896-6273

issn

1097-4199

pii

S0896-6273(14)00647-3

journal_volume

83

pub_type

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