Utilize este identificador para referenciar este registo:
https://hdl.handle.net/1822/62020
Registo completo
Campo DC | Valor | Idioma |
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dc.contributor.author | Zemel, Benjamin M. | por |
dc.contributor.author | Muqeem, Tanziyah | por |
dc.contributor.author | Brown, Eric V. | por |
dc.contributor.author | Goulão, Miguel | por |
dc.contributor.author | Urban, Mark W. | por |
dc.contributor.author | Tymanskyj, Stephen R. | por |
dc.contributor.author | Lepore, Angelo C. | por |
dc.contributor.author | Covarrubias, Manuel | por |
dc.date.accessioned | 2019-11-11T14:12:09Z | - |
dc.date.issued | 2017 | - |
dc.identifier.issn | 0270-6474 | - |
dc.identifier.uri | https://hdl.handle.net/1822/62020 | - |
dc.description.abstract | 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. | por |
dc.description.sponsorship | This work was supported by the Vickie and Jack Farber Family Foundation (M.C.), the Dean’s Transformational Science Award(M.C.), andtheNational Institutes ofHealth(GrantNS090689to B.M.Z. and GrantNS079855toM.C.). | por |
dc.language.iso | eng | por |
dc.publisher | Society for Neuroscience | por |
dc.rights | restrictedAccess | por |
dc.subject | Animals | por |
dc.subject | CHO Cells | por |
dc.subject | Calcineurin | por |
dc.subject | Calcineurin Inhibitors | por |
dc.subject | Cells, Cultured | por |
dc.subject | Cervical Vertebrae | por |
dc.subject | Cricetinae | por |
dc.subject | Cricetulus | por |
dc.subject | Female | por |
dc.subject | Ganglia, Spinal | por |
dc.subject | Neurons | por |
dc.subject | Potassium Channels, Voltage-Gated | por |
dc.subject | Rats | por |
dc.subject | Rats, Sprague-Dawley | por |
dc.subject | Shaw Potassium Channels | por |
dc.subject | Spinal Cord Injuries | por |
dc.subject | Kv3.4 | por |
dc.subject | Pain | por |
dc.subject | RCAN1 | por |
dc.subject | spinal cord injury | por |
dc.title | Calcineurin dysregulation underlies spinal cord injury-induced K+ channel dysfunction in DRG neurons | por |
dc.type | article | por |
dc.peerreviewed | yes | por |
oaire.citationStartPage | 8256 | por |
oaire.citationEndPage | 8272 | por |
oaire.citationIssue | 34 | por |
oaire.citationVolume | 37 | por |
dc.identifier.eissn | 1529-2401 | - |
dc.identifier.doi | 10.1523/JNEUROSCI.0434-17.2017 | por |
dc.date.embargo | 10000-01-01 | - |
dc.identifier.pmid | 28751455 | por |
dc.subject.wos | Science & Technology | por |
sdum.journal | Journal of Neuroscience | por |
Aparece nas coleções: | ICVS - Artigos em revistas internacionais / Papers in international journals |
Ficheiros deste registo:
Ficheiro | Descrição | Tamanho | Formato | |
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Zemel-2017-Calcineurin-dysregulation-underlies.pdf Acesso restrito! | 4,93 MB | Adobe PDF | Ver/Abrir |