Carbon monoxide inhibition of Cav3.2 T-type Ca2+ channels reveals tonic modulation by thioredoxin.
FASEB J
; 27(8): 3395-407, 2013 Aug.
Article
em En
| MEDLINE
| ID: mdl-23671274
ABSTRACT
T-type Ca(2+) channels play diverse roles in tissues such as sensory neurons, vascular smooth muscle, and cancers, where increased expression of the cytoprotective enzyme, heme oxygenase-1 (HO-1) is often found. Here, we report regulation of T-type Ca(2+) channels by carbon monoxide (CO) a HO-1 by-product. CO (applied as CORM-2) caused a concentration-dependent, poorly reversible inhibition of all T-type channel isoforms (Cav3.1-3.3, IC50 â¼3 µM) expressed in HEK293 cells, and native T-type channels in NG108-15 cells and primary rat sensory neurons. No recognized CO-sensitive signaling pathway could account for the CO inhibition of Cav3.2. Instead, CO sensitivity was mediated by an extracellular redox-sensitive site, which was also highly sensitive to thioredoxin (Trx). Trx depletion (using auranofin, 2-5 µM) reduced Cav3.2 currents and their CO sensitivity by >50% but increased sensitivity to dithiothreitol â¼3-fold. By contrast, Cav3.1 and Cav3.3 channels, and their sensitivity to CO, were unaffected in identical experiments. Our data propose a novel signaling pathway in which Trx acts as a tonic, endogenous regulator of Cav3.2 channels, while HO-1-derived CO disrupts this regulation, causing channel inhibition. CO modulation of T-type channels has widespread implications for diverse physiological and pathophysiological mechanisms, such as excitability, contractility, and proliferation.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tiorredoxinas
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Dióxido de Carbono
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Ativação do Canal Iônico
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Canais de Cálcio Tipo T
Limite:
Animals
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Humans
Idioma:
En
Revista:
FASEB J
Assunto da revista:
BIOLOGIA
/
FISIOLOGIA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Reino Unido