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
Neuronjournal_title
Neuronauthors
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 GWdoi
10.1016/j.neuron.2014.07.036subject
Has Abstractpub_date
2014-09-03 00:00:00pages
1144-58issue
5eissn
0896-6273issn
1097-4199pii
S0896-6273(14)00647-3journal_volume
83pub_type
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