The Deubiquitinating Enzyme USP5 Modulates Neuropathic and Inflammatory Pain by Enhancing Ca(v)3.2 Channel Activity

作者：Garcia Caballero Agustin; Gadotti Vinicius M; Stemkowski Patrick; Weiss Norbert; Souza Ivana A; Hodgkinson Victoria; Bladen Chris; Chen Lina; Hamid Jawed; Pizzoccaro Anne; Deage Mickael; Francois Amaury; Bourinet Emmanuel; Zamponi Gerald W^*

来源：Neuron, 2014, 83(5): 1144-1158.

DOI：10.1016/j.neuron.2014.07.036

T-type calciumchannels 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 Ca(v)3.2 T-type channel and modifies specific lysine residues in this region. A proteomic screen identified the deubiquitinating enzyme USP5 as a Ca(v)3.2 III-IV linker interacting partner. Knockdown of USP5 via shRNA increases Ca(v)3.2 ubiquitination, decreases Ca(v)3.2 protein levels, and reduces Ca(v)3.2 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.

• 出版日期2014-9-3