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

León-Paravic, Carmen G.; Figueroa, Vania; Guzmán, Diego J.; Valderrama, Carlos F.; Vallejos, Antonio A.; Fiori, Mariana C.; Altenberg, Guillermo A.; Reuss, Luis; Retamal, Mauricio A.

doi:10.1074/jbc.m114.602243

Cited by 28 publications

(33 citation statements)

References 44 publications

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“…Thus, we hypothesized that both intracellular and extracellular Cys control some hemichannel properties by changing their redox status (Figure 2 ). Accordingly, carbon monoxide (CO), which is another gaseous transmitter that modulates the redox status in cells, induced an important current reduction of Cx46 hemichannels (León-Paravic et al, 2014 ). This effect was observed in Xenopus laevis oocytes expressing a Cx46 mutant lacking intracellular Cys (Cx46C3A), but was absent in oocytes expressing a Cx46 Cys-lacking mutant (Cx46CL), suggesting that extracellular Cys is/are important(s) for the inhibition of Cx46 hemichannels induced by CO.…”

Section: Extracellular Vs Intracellular Connexin Cysteines: Their Romentioning

confidence: 99%

“…Interestingly, current evidence allows us to suggest that there is a pool of hemichannels at the plasma membrane with reduced extracellular Cys, which allows them to open frequently. When these reduced Cys become oxidized (e.g., forming disulfide bonds or carbonylated; León-Paravic et al, 2014 ), hemichannels become mostly closed. Green dots represent Cys oxidized by free radicals such as ROS, RNS or carbon monoxide (CO).…”

Section: Extracellular Vs Intracellular Connexin Cysteines: Their Romentioning

confidence: 99%

“…Once in the extracellular space, TRx is able to reduce disulfide bonds to -SHs recovering its reducing power; and oxidized TRx is reduced by the NADPH dependent flavoenzyme thioredoxin reductase (TRxR) (Matsuo and Yodoi, 2013 ). Until now, no direct effect of TRx or any other enzyme relate to redox control on astrocytic hemichannels has been found, but it has been suggested that at least Trx may participate in the decarbonylation process observed in Cx46 after carbon monoxide exposure (León-Paravic et al, 2014 ). Therefore, it is evident that more research is needed about the role of redox control upon hemichannels under physiological conditions in brains cells.…”

Section: Possible Implications Of Hemichannel Redox Modulationmentioning

confidence: 99%

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Extracellular Cysteine in Connexins: Role as Redox Sensors

et al. 2016

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Connexin-based channels comprise hemichannels and gap junction channels. The opening of hemichannels allow for the flux of ions and molecules from the extracellular space into the cell and vice versa. Similarly, the opening of gap junction channels permits the diffusional exchange of ions and molecules between the cytoplasm and contacting cells. The controlled opening of hemichannels has been associated with several physiological cellular processes; thereby unregulated hemichannel activity may induce loss of cellular homeostasis and cell death. Hemichannel activity can be regulated through several mechanisms, such as phosphorylation, divalent cations and changes in membrane potential. Additionally, it was recently postulated that redox molecules could modify hemichannels properties in vitro. However, the molecular mechanism by which redox molecules interact with hemichannels is poorly understood. In this work, we discuss the current knowledge on connexin redox regulation and we propose the hypothesis that extracellular cysteines could be important for sensing changes in redox potential. Future studies on this topic will offer new insight into hemichannel function, thereby expanding the understanding of the contribution of hemichannels to disease progression.

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Section: Extracellular Vs Intracellular Connexin Cysteines: Their Romentioning

confidence: 99%

Section: Extracellular Vs Intracellular Connexin Cysteines: Their Romentioning

confidence: 99%

Section: Possible Implications Of Hemichannel Redox Modulationmentioning

confidence: 99%

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Extracellular Cysteine in Connexins: Role as Redox Sensors

et al. 2016

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“…; ref. ). León‐Paravic et al showed that a CO donor (CORM‐2) induced a dose‐response inhibition in Cx46 hemichannels expressed in Xenopus laevis oocytes.…”

Section: Carbon Monoxide Modulates CX Hemichannelsmentioning

confidence: 97%

“…In general terms, an increase of CO concentration has been associated to protective cellular effects , whereas increases in NO concentration have been associated to deleterious effects . According to this, the addition of NO donors to astrocytes in culture induces a massive Cx43 hemichannel opening ; however, when a CO donor is added to HeLa cells, Cx43 hemichannel became closed . However, it is unknown whether astrocytes exposed to CO donors also close their Cx43 hemichannels, and whether the effect of NO and CO over Cx43 hemichannels is synergic or antagonic is also unknown.…”

Section: Possible Interplay Between Co and No In CX Hemichannel Activitymentioning

confidence: 99%

Carbon monoxide: A new player in the redox regulation of connexin hemichannels

et al. 2015

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Carbon monoxide (CO) is a gaseous transmitter that is known to be involved in several physiological processes, but surprisingly it is also becoming a promising molecule to treat several pathologies including stroke and cancer. CO can cross the plasma membrane and activate guanylate cyclase, increasing the cGMP concentration and activating some kinases, including PKG. The other mechanism of action involves induction of protein carbonylation. CO is known to directly and indirectly modulate the function of ion channels at the plasma membrane, which in turn have important repercussions in the cellular behavior. One group of these channels is hemichannels, which are formed by proteins known as connexins (Cxs). Hemichannel allows not only the flow of ions through their pore but also the release of molecules such as ATP and glutamate. Therefore, their modulation not only impacts cellular function but also cellular communication, having the capability to affect tissular behavior. Here, we review the most recent results regarding the effect of CO on Cx hemichannels and their possible repercussions on pathologies. V C 2015 IUBMB Life, 67(6): [428][429][430][431][432][433][434][435][436][437] 2015

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Gaseous Signaling Molecules in Cardiovascular Function: From Mechanisms to Clinical Translation

Lee

Nilius

Han

2018

Reviews of Physiology, Biochemistry and Pharmacology

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Carbon monoxide (CO), hydrogen sulfide (HS), and nitric oxide (NO) constitute endogenous gaseous molecules produced by specific enzymes. These gases are chemically simple, but exert multiple effects and act through shared molecular targets to control both physiology and pathophysiology in the cardiovascular system (CVS). The gases act via direct and/or indirect interactions with each other in proteins such as heme-containing enzymes, the mitochondrial respiratory complex, and ion channels, among others. Studies of the major impacts of CO, HS, and NO on the CVS have revealed their involvement in controlling blood pressure and in reducing cardiac reperfusion injuries, although their functional roles are not limited to these conditions. In this review, the basic aspects of CO, HS, and NO, including their production and effects on enzymes, mitochondrial respiration and biogenesis, and ion channels are briefly addressed to provide insight into their biology with respect to the CVS. Finally, potential therapeutic applications of CO, HS, and NO with the CVS are addressed, based on the use of exogenous donors and different types of delivery systems.

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

Cited by 28 publications

References 44 publications

Extracellular Cysteine in Connexins: Role as Redox Sensors

Extracellular Cysteine in Connexins: Role as Redox Sensors

Carbon monoxide: A new player in the redox regulation of connexin hemichannels

Gaseous Signaling Molecules in Cardiovascular Function: From Mechanisms to Clinical Translation

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