Carbon Monoxide (CO) Is a Novel Inhibitor of Connexin Hemichannels

Leon-Paravic C.G.; Figueroa V.A.; Guzman D.J.; Valderrama C.F.; Vallejos A.A.; Fiori M.C.; Altenberg G.A.; Reuss L.; Retamal M.A.

Abstract

Hemichannels (HCs) are hexamers of connexins that can form gap-junction channels at points of cell contacts or free HCs at non-contacting regions. HCs are involved in paracrine and autocrine cell signaling, and under pathological conditions may induce and/or accelerate cell death. Therefore, studies of HC regulation are of great significance. Nitric oxide affects the activity of Cx43 and Cx46 HCs, whereas carbon monoxide (CO), another gaseous transmitter, modulates the activity of several ion channels, but its effect on HCs has not been explored. We studied the effect of CO donors (CORMs) on Cx46 HCs expressed in Xenopus laevis oocytes using two-electrode voltage clamp and on Cx43 and Cx46 expressed in HeLa cells using a dye-uptake technique. CORM-2 inhibited Cx46 HC currents in a concentration-dependent manner. The C-terminal domain and intracellular Cys were not necessary for the inhibition. The effect of CORM-2 was not prevented by guanylyl-cyclase, protein kinase G, or thioredoxin inhibitors, and was not due to endocytosis of HCs. However, the effect of CORM-2 was reversed by reducing agents that act extracellularly. Additionally, CO inhibited dye uptake of HeLa cells expressing Cx43 or Cx46, and MCF-7 cells, which endogenously express Cx43 and Cx46. Because CORM-2 carbonylates Cx46 in vitro and induces conformational changes, a direct effect of that CO on Cx46 is possible. The inhibition of HCs could help to understand some of the biological actions of CO in physiological and pathological conditions.

Más información

Título según WOS: Carbon Monoxide (CO) Is a Novel Inhibitor of Connexin Hemichannels
Título según SCOPUS: Carbon monoxide (CO) is a novel inhibitor of connexin hemichannels
Título de la Revista: JOURNAL OF BIOLOGICAL CHEMISTRY
Volumen: 289
Asunto: 52
Editorial: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Fecha de publicación: 2014-01-01
Página de inicio: 36150
Página final: 36157
Idioma: English
DOI/URL:

10.1074/jbc.M114.602243

Identificador: 10.1074/jbc.M114.602243
Notas: ISI, SCOPUS