Inhibition of the Cardiac Na+ Channel Nav1.5 by Carbon Monoxide

Elíes, Jacobo; Dallas, Mark L.; Boyle, John P.; Scragg, Jason L.; Duke, Adrian M.; Steele, Derek S.; Peers, Chris

doi:10.1074/jbc.m114.569996

Cited by 19 publications

(18 citation statements)

References 51 publications

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“… 63 Peak inward Na + current inhibition by CO is also NO dependent. 64 Inhibition of the cardiac L-type Ca 2+ current by CO is dependent on mitochondrial ROS production but independent of NO formation. 65 Most recently, we have shown that cardiac ERG (Kv11.1) channels are also inhibited by CO, specifically via the formation of ONOO − .…”

Section: Discussionmentioning

confidence: 99%

Multiple mechanisms mediating carbon monoxide inhibition of the voltage-gated K+ channel Kv1.5

et al. 2017

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The voltage-gated K+ channel has key roles in the vasculature and in atrial excitability and contributes to apoptosis in various tissues. In this study, we have explored its regulation by carbon monoxide (CO), a product of the cytoprotective heme oxygenase enzymes, and a recognized toxin. CO inhibited recombinant Kv1.5 expressed in HEK293 cells in a concentration-dependent manner that involved multiple signalling pathways. CO inhibition was partially reversed by superoxide dismutase mimetics and by suppression of mitochondrial reactive oxygen species. CO also elevated intracellular nitric oxide (NO) levels. Prevention of NO formation also partially reversed CO inhibition of Kv1.5, as did inhibition of soluble guanylyl cyclase. CO also elevated intracellular peroxynitrite levels, and a peroxynitrite scavenger markedly attenuated the ability of CO to inhibit Kv1.5. CO caused nitrosylation of Kv1.5, an effect that was also observed in C331A and C346A mutant forms of the channel, which had previously been suggested as nitrosylation sites within Kv1.5. Augmentation of Kv1.5 via exposure to hydrogen peroxide was fully reversed by CO. Native Kv1.5 recorded in HL-1 murine atrial cells was also inhibited by CO. Action potentials recorded in HL-1 cells were increased in amplitude and duration by CO, an effect mimicked and occluded by pharmacological inhibition of Kv1.5. Our data indicate that Kv1.5 is a target for modulation by CO via multiple mechanisms. This regulation has important implications for diverse cellular functions, including excitability, contractility and apoptosis.

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Section: Discussionmentioning

confidence: 99%

Multiple mechanisms mediating carbon monoxide inhibition of the voltage-gated K+ channel Kv1.5

et al. 2017

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“…Indeed, the literature contains several reports of nonheme targets of CO ( 31 ), including examples of nonheme iron(II) carbonyls, including metals coordinated to S from cysteine and/or N from histidine. These ligands may constitute targets in cation channels ( 21 ) or in bacterial ion channels, leading to subsequent respiratory stimulation ( 74 ). Other examples of nonheme interactions include CO binding to iron in [Fe]-, [Fe-Fe]- and [Fe-Ni]-hydrogenases as in Chlamydomonas ( 66 ).…”

Section: Introductionmentioning

confidence: 99%

CO-Releasing Molecules Have Nonheme Targets in Bacteria: Transcriptomic, Mathematical Modeling and Biochemical Analyses of CORM-3 [Ru(CO)₃Cl(glycinate)] Actions on a Heme-Deficient Mutant ofEscherichia coli

Wilson

Wareham

Mclean

et al. 2015

Antioxidants & Redox Signaling

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Aims: Carbon monoxide-releasing molecules (CORMs) are being developed with the ultimate goal of safely utilizing the therapeutic potential of CO clinically, including applications in antimicrobial therapy. Hemes are generally considered the prime targets of CO and CORMs, so we tested this hypothesis using heme-deficient bacteria, applying cellular, transcriptomic, and biochemical tools. Results: CORM-3 [Ru(CO)3Cl(glycinate)] readily penetrated Escherichia coli hemA bacteria and was inhibitory to these and Lactococcus lactis, even though they lack all detectable hemes. Transcriptomic analyses, coupled with mathematical modeling of transcription factor activities, revealed that the response to CORM-3 in hemA bacteria is multifaceted but characterized by markedly elevated expression of iron acquisition and utilization mechanisms, global stress responses, and zinc management processes. Cell membranes are disturbed by CORM-3. Innovation: This work has demonstrated for the first time that CORM-3 (and to a lesser extent its inactivated counterpart) has multiple cellular targets other than hemes. A full understanding of the actions of CORMs is vital to understand their toxic effects. Conclusion: This work has furthered our understanding of the key targets of CORM-3 in bacteria and raises the possibility that the widely reported antimicrobial effects cannot be attributed to classical biochemical targets of CO. This is a vital step in exploiting the potential, already demonstrated, for using optimized CORMs in antimicrobial therapy. Antioxid. Redox Signal. 23, 148–162.

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“…The molecular mechanism of this phenomenon is not well understood, but it has been proposed that depends on the increase of the number of Ca 2+ binding sites (Wang et al, 1997 ), expression of the alpha subunit (Wu et al, 2002 ), modulation by NO (Wang and Wu, 2003 ), and a metal-dependent like coordination of CO by Cys at position 911 (C911) (Williams et al, 2008 ; Telezhkin et al, 2011 ). Other ion channels are also affected by CO, such as a 70-pS K + channel in the thick ascending limb of Henle's loop (Liu et al, 1999 ), Kv2.1 (Dallas et al, 2011 ), hTREK-1 (Dallas et al, 2008 ), the amiloride-sensitive Na + channel (Althaus et al, 2009 ), Nav1.5 channels (Elies et al, 2014 ), Cav3.2 (Boycott et al, 2013 ), and P2X2 receptors (Wilkinson et al, 2009 ). In the case of Cav3.2 channels, CO induced-inhibition was dependent on the activation of an extracellular thioredoxin-dependent mechanism (Scragg et al, 2008 ).…”

Section: Carbon Monoxide Modulates Ion Channelsmentioning

confidence: 99%

Carbon Monoxide Modulates Connexin Function through a Lipid Peroxidation-Dependent Process: A Hypothesis

Retamal

2016

Front. Physiol.

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Hemichannels are ion channels composed of six connexins (Cxs), and they have the peculiarity to be permeable not only to ions, but also to molecules such as ATP and glutamate. Under physiological conditions they present a low open probability, which is sufficient to enable them to participate in several physiological functions. However, massive and/or prolonged hemichannel opening induces or accelerates cell death. Therefore, the study of the molecular mechanisms that control hemichannel activity appears to be essential for understanding several physiological and pathological processes. Carbon monoxide (CO) is a gaseous transmitter that modulates many cellular processes, some of them through modulation of ion channel activity. CO exerts its biological actions through the activation of guanylate cyclase and/or inducing direct carbonylation of proline, threonine, lysine, and arginine. It is well accepted that guanylate cyclase dependent pathway and direct carbonylation, are not sensitive to reducing agents. However, it is important to point out that CO—through a lipid peroxide dependent process—can also induce a secondary carbonylation in cysteine groups, which is sensitive to reducing agents. Recently, in our laboratory we demonstrated that the application of CO donors to the bath solution inhibited Cx46 hemichannel currents in Xenopus laevis oocytes, a phenomenon that was fully reverted by reducing agents. Therefore, a plausible mechanism of CO-induced Cx46 hemichannel inhibition is through Cx46-lipid oxidation. In this work, I will present current evidence and some preliminary results that support the following hypothesis: Carbon monoxide inhibits Cx46 HCs through a lipid peroxidation-dependent process. The main goal of this paper is to broaden the scientific community interest in studying the relationship between CO-Fatty acids and hemichannels, which will pave the way to more research directed to the understanding of the molecular mechanism(s) that control the opening and closing of hemichannels in both physiological and pathological conditions.

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Inhibition of the Cardiac Na+ Channel Nav1.5 by Carbon Monoxide

Cited by 19 publications

References 51 publications

Multiple mechanisms mediating carbon monoxide inhibition of the voltage-gated K+ channel Kv1.5

Multiple mechanisms mediating carbon monoxide inhibition of the voltage-gated K+ channel Kv1.5

CO-Releasing Molecules Have Nonheme Targets in Bacteria: Transcriptomic, Mathematical Modeling and Biochemical Analyses of CORM-3 [Ru(CO)₃Cl(glycinate)] Actions on a Heme-Deficient Mutant ofEscherichia coli

Carbon Monoxide Modulates Connexin Function through a Lipid Peroxidation-Dependent Process: A Hypothesis

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Inhibition of the Cardiac Na+ Channel Nav1.5 by Carbon Monoxide

Cited by 19 publications

References 51 publications

Multiple mechanisms mediating carbon monoxide inhibition of the voltage-gated K+ channel Kv1.5

Multiple mechanisms mediating carbon monoxide inhibition of the voltage-gated K+ channel Kv1.5

CO-Releasing Molecules Have Nonheme Targets in Bacteria: Transcriptomic, Mathematical Modeling and Biochemical Analyses of CORM-3 [Ru(CO)3Cl(glycinate)] Actions on a Heme-Deficient Mutant ofEscherichia coli

Carbon Monoxide Modulates Connexin Function through a Lipid Peroxidation-Dependent Process: A Hypothesis

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CO-Releasing Molecules Have Nonheme Targets in Bacteria: Transcriptomic, Mathematical Modeling and Biochemical Analyses of CORM-3 [Ru(CO)₃Cl(glycinate)] Actions on a Heme-Deficient Mutant ofEscherichia coli