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Calcineurin dysregulation underlies spinal cord injury-induced K+ channel dysfunction in DRG neurons

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Resumo:Dysfunction of the fast-inactivating Kv3.4 potassium current in dorsal root ganglion (DRG) neurons contributes to the hyperexcitability associated with persistent pain induced by spinal cord injury (SCI). However, the underlying mechanism is not known. In light of our previous work demonstrating modulation ofthe Kv3.4 channel by phosphorylation, we investigatedthe role ofthe phosphatase calcineurin (CaN) using electrophysiological, molecular, and imaging approaches in adult female Sprague Dawley rats. Pharmacological inhibition of CaN in small-diameter DRG neurons slowed repolarization of the somatic action potential (AP) and attenuated the Kv3.4 current. Attenuated Kv3.4 currents also exhibited slowed inactivation. We observed similar effects on the recombinant Kv3.4 channel heterologously expressedin Chinese hamster ovary cells, supporting ourfindingsin DRG neurons. Elucidatingthemolecular basis ofthese effects, mutation of four previously characterized serines within the Kv3.4 N-terminal inactivation domain eliminated the effects of CaN inhibition on the Kv3.4 current. SCI similarly induced concurrent Kv3.4 current attenuation and slowing of inactivation. Although there was little change in CaN expression and localization after injury, SCI induced upregulation of the native regulator of CaN 1 (RCAN1) in the DRG at the transcript and protein levels. Consistent with CaN inhibition resulting from RCAN1 upregulation, overexpression of RCAN1 in naive DRG neurons recapitulated the effects of pharmacological CaN inhibition on the Kv3.4 current and the AP. Overall, these results demonstrate a novel regulatory pathwaythat links CaN, RCAN1, and Kv3.4in DRG neurons. Dysregulation ofthis pathway might underlie a peripheral mechanism of pain sensitization induced by SCI.
Autores principais:Zemel, Benjamin M.
Outros Autores:Muqeem, Tanziyah; Brown, Eric V.; Goulão, Miguel; Urban, Mark W.; Tymanskyj, Stephen R.; Lepore, Angelo C.; Covarrubias, Manuel
Assunto:Animals CHO Cells Calcineurin Calcineurin Inhibitors Cells, Cultured Cervical Vertebrae Cricetinae Cricetulus Female Ganglia, Spinal Neurons Potassium Channels, Voltage-Gated Rats Rats, Sprague-Dawley Shaw Potassium Channels Spinal Cord Injuries Kv3.4 Pain RCAN1 spinal cord injury
Ano:2017
País:Portugal
Tipo de documento:artigo
Tipo de acesso:acesso restrito
Instituição associada:Universidade do Minho
Idioma:inglês
Origem:RepositóriUM - Universidade do Minho

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