Glutathione release through connexin hemichannels: Implications for chemical modification of pores permeable to large molecules

Tong, Xuhui; Lopez, William; Ramachandran, Jayalakshmi; Ayad, Wafaa A.; Liu, Yu; Lopez-Rodriguez, Angélica; Harris, Andrew L.; Contreras, Jorge E.

doi:10.1085/jgp.201511375

Cited by 24 publications

(21 citation statements)

References 38 publications

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“…The relevance of this finding remains unclear. Alternatively, cytosolic GSH may be liberated through Cx32 and Cx43 hemichannels, thus jeopardizing anti-oxidant cellular defense (Keleva et al 2013; Rana and Dringen, 2007; Tong et al, 2015). However, the results of the current study do not seem in line with this scenario, as no differences were found in GSH amounts between the different experimental groups after 3 and 24 hours (Fig.…”

Section: Discussionmentioning

confidence: 99%

Connexin hemichannel inhibition reduces acetaminophen-induced liver injury in mice

et al. 2017

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Historically, connexin hemichannels have been considered as structural precursors of gap junctions. However, accumulating evidence points to independent roles for connexin hemichannels in cellular signaling by connecting the intracellular compartment with the extracellular environment. Unlike gap junctions, connexin hemichannels seem to be mainly activated in pathological processes. The present study was set up to test the potential involvement of hemichannels composed of connexin32 and connexin43 in acute hepatotoxicity induced by acetaminophen. Prior to this, in vitro testing was performed to confirm the specificity and efficiency of TAT-Gap24 and TAT-Gap19 in blocking connexin32 and connexin43 hemichannels, respectively. Subsequently, mice were overdosed with acetaminophen followed by treatment with TAT-Gap24 or TAT-Gap19 or a combination of both after 1.5 hour. Sampling was performed 3, 6, 24 and 48 hours following acetaminophen administration. Evaluation of the effects of connexin hemichannel inhibition was based on a series of clinically relevant read-outs, measurement of inflammatory cytokines and oxidative stress. Subsequent treatment of acetaminophen-overdosed mice with TAT-Gap19 only marginally affected liver injury. In contrast, a significant reduction in serum alanine aminotransferase activity was found upon administration of TAT-Gap24 to intoxicated animals. Furthermore, co-treatment of acetaminophen-overdosed mice with both peptides revealed an additive effect as even lower serum alanine aminotransferase activity was observed. Blocking of connexin32 or connexin43 hemichannels individually was found to decrease serum quantities of pro-inflammatory cytokines, while no effects were observed on the occurrence of hepatic oxidative stress. This study shows for the first time a role for connexin hemichannels in acetaminophen-induced acute liver failure.

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Section: Discussionmentioning

confidence: 99%

Connexin hemichannel inhibition reduces acetaminophen-induced liver injury in mice

et al. 2017

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“…Regarding the latter, Igarashi and group found less decreased GSH and GSSG levels in APAP-treated Cx32 knock-out mice and attributed the protective effect of Cx32 against liver injury to changes in GSH transmission between hepatocytes (Igarashi et al 2014). GSH indeed is known to permeate gap junctions and it has been reported that hemichannels, including those based on Cx32, can also transport GSH (Rana and Dringen 2007; Tong et al 2015). At the more upstream mechanistic platform of APAP toxicity, cell death results from protein adduct formation involving NAPQI.…”

Section: Discussionmentioning

confidence: 99%

Connexin32: a mediator of acetaminophen-induced liver injury?

Maes

McGill

Silva

et al. 2016

Toxicology Mechanisms and Methods

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Connexin32 is the building block of hepatocellular gap junctions, which control direct intercellular communication and thereby act as goalkeepers of liver homeostasis. This study was set up to investigate whether connexin32 is involved in hepatotoxicity induced by the analgesic and antipyretic drug acetaminophen. To this end, whole body connexin32 knock-out mice were overdosed with acetaminophen followed by sampling at different time points within a 24-hour time frame. Evaluation was done based upon a series of clinically and mechanistically relevant read-outs, including protein adduct formation, histopathological examination, measurement of alanine aminotransferase activity, cytokine production, levels of reduced and oxidized glutathione, and hepatic protein amounts of proliferating cell nuclear antigen. In essence, it was found that genetic ablation of connexin32 has no influence on several key events in acetaminophen-induced hepatotoxicity, including cell death, inflammation or oxidative stress, yet it does affect production of protein adducts as well as proliferating cell nuclear antigen steady-state protein levels. This outcome is not in line with previous studies, which are contradicting on their own, as both amplification and alleviation of this toxicological process by connexin32 have been described. This could question the suitability of the currently available models and tools to investigate the role of connexin32 in acetaminophen-triggered hepatotoxicity.

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“…Previous studies have shown that connexin hemichannels are permeable to glutathione (GSH) (Slavi et al, 2014;Stridh et al, 2008;Tong et al, 2015). Given that the GSH concentration in vitreous humor is unusually high and hemichannels transport molecules with sizes no more than 1 kDa, we tested the hypothesis that opening of hemichannels in response to oxidative stress facilitates entry of GSH into the cell and protects cells against oxidative damage.…”

Section: Hemichannels Mediate Cellular Uptake Of Glutathione and Protmentioning

confidence: 99%

Connexin hemichannels mediate glutathione transport and protect lens fiber cells from oxidative stress

Shi

Riquelme

et al. 2018

Journal of Cell Science

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Elevated oxidized stress contributes to lens cataracts, and gap junctions play important roles in maintaining lens transparency. As well as forming gap junctions, connexin (Cx) proteins also form hemichannels. Here, we report a new mechanism whereby hemichannels mediate transport of reductant glutathione into lens fiber cells and protect cells against oxidative stress. We found that Cx50 (also known as GJA8) hemichannels opened in response to HO in lens fiber cells but that transport through the channels was inhibited by two dominant-negative mutants in Cx50, Cx50P88S, which inhibits transport through both gap junctions and hemichannels, and Cx50H156N, which only inhibits transport through hemichannels and not gap junctions. Treatment with HO increased the number of fiber cells undergoing apoptosis, and this increase was augmented with dominant-negative mutants that disrupted both hemichannels formed from Cx46 (also known as GJA3) and Cx50, while Cx50E48K, which only impairs gap junctions, did not have such an effect. Moreover, hemichannels mediate uptake of glutathione, and this uptake protected lens fiber cells against oxidative stress, while hemichannels with impaired transport had less protective benefit from glutathione. Taken together, these results show that oxidative stress activates connexin hemichannels in the lens fiber cells and that hemichannels likely protect lens cell against oxidative damage through transporting extracellular reductants.

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Glutathione release through connexin hemichannels: Implications for chemical modification of pores permeable to large molecules

Abstract: The cytosolic reducing agent glutathione can reverse thiol modification of cysteine residues inside the pores of connexins and other channels permeable to large molecules.

Cited by 24 publications

References 38 publications

Connexin hemichannel inhibition reduces acetaminophen-induced liver injury in mice

Connexin hemichannel inhibition reduces acetaminophen-induced liver injury in mice

Connexin32: a mediator of acetaminophen-induced liver injury?

Connexin hemichannels mediate glutathione transport and protect lens fiber cells from oxidative stress

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