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

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

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, studi...

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Bibliographic Details
Published in:The Journal of biological chemistry Vol. 289; no. 52; pp. 36150 - 36157
Main Authors: León-Paravic, Carmen G., Figueroa, Vania A., Guzmán, Diego J., Valderrama, Carlos F., Vallejos, Antonio A., Fiori, Mariana C., Altenberg, Guillermo A., Reuss, Luis, Retamal, Mauricio A.
Format: Journal Article
Language:English
Published: United States Elsevier Inc 26-12-2014
American Society for Biochemistry and Molecular Biology
Subjects:
Animals
Carbon Monoxide
Carbon Monoxide - pharmacology
Carbonylation
Cell Biology
Connexin
Connexin 43 - antagonists & inhibitors
Connexin 43 - metabolism
Connexins - antagonists & inhibitors
Connexins - metabolism
Glutathione - pharmacology
HeLa Cells
Hemichannels
Humans
Ion Channel
MCF-7 Cells
Membrane Potentials
Organometallic Compounds - pharmacology
Post-translational Modification (PTM)
Protein Carbonylation
Redox Signaling
Reducing Agents - pharmacology
Xenopus laevis
Connexin
Carbonylation
Hemichannels
Carbon Monoxide
Ion Channel
Post-translational Modification (PTM)
Redox Signaling
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Summary: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.Carbon monoxide and connexin hemichannels are involved in several physiological and pathological processes. Carbon monoxide inhibits Cx43 and Cx46 hemichannel opening. Connexin hemichannels are modulated by gaseous transmitters. Our observations will help understand the effects of CO and CO donors in pathological conditions.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M114.602243