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

Abstract

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.

Use of Enzymatically Activated Carbon Monoxide Donors for Sensitizing Drug-Resistant Tumor Cells

“…This damage can be caused by mtROS produced or directly by CO, as previously reported [10]. Mitochondrial ROS [16] and lipid peroxidation [41] are two conditions suggestive of ferroptosis, a type of cell death independent of caspase activation but triggered by oxidative stress, often catalyzed by iron or promoted by reduced antioxidant defenses or immune signaling from tumor microenvironment [42]. Because we detected either oxidative stress and lipoperoxidation in cells treated with CORM and chemotherapeutic drugs, we cannot exclude that CORM acted by inducing ferroptotic death.…”

“…This effect may be attributed to the direct inhibition of mitochondrial complex IV by CO [16] and/or increased accumulation of chemotherapeutic drugs within cells, caused by reduced mtATP production. Alternatively, as already observed for NO and H 2 S [5][6][7], CO may also directly reduce the activity of ABC transporters: it has been reported that CO oxidizes the cysteines of integral membrane proteins, triggering a radical cascade at the membrane protein-lipid interface that alters protein functions [41]. Our CO-donor also induced a reduction in the catalytic efficacy of ABCB1, ABCC1 and ABCC5 in cell lines with the highest levels of these transporters, suggesting a lower efficiency in efflux of the respective chemotherapeutic substrates.…”

Role of ROS/RNS in Preeclampsia: Are Connexins the Missing Piece?

“…Our group and others have proposed that molecules associated to oxidative stress modulate hemichannel opening [70,[83][84][85][86]. For example, Cx43 hemichannel S-nitrosylation exacerbates hemichannel activity in cerebral ischemia [87] and inflammatory models [62].…”

Role and Posttranslational Regulation of Cx46 Hemichannels and Gap Junction Channels in the Eye Lens

“…We also found that CORM-2 induces carbonylation of purified Cx46 ( Leon-Paravic et al, 2014 ), but the amino acids modified have not been identified. Based on these observations, we have proposed that CO carbonylates extracellular Cx46 cysteines through lipid peroxides, which reduces Cx46 hemichannel activity, with a protective effect against oxidative stress and cataract development ( Retamal, 2016 ).…”