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Front Physiol
2016 Jun 28;7:259. doi: 10.3389/fphys.2016.00259.
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Carbon Monoxide Modulates Connexin Function through a Lipid Peroxidation-Dependent Process: A Hypothesis.
Retamal MA
.
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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.
Figure 1. The above diagram presents what is proposed as a possible molecular mechanism to explain the CO-induced Cx46 inhibition. CO increases free radicals concentration (1) which in turn induces lipid peroxide production (2). Then, lipid peroxides can induce the carbonylation of extracellular cysteine (-SH) (3), increasing Cx46-Ca2+ sensitivity (4) and thus stabilizing the closed state of the loop gating (5).
Figure 2. CO effect appears to be mediated by lipid peroxides. (A) Representative control of Cx46 hemichannel currents in Xenopus laevis oocytes recorded in ND96 solution (containing 1.8 mM Ca2+ and 1.0 mM Mg2+) by means of dual whole cell voltage clamp technique. The presence of 100 μM CORM-2 induces a dramatic drop in the current amplitude. Most of the inhibition induced by CORM-2 was prevented by the co-addition of 100 μM ascorbic acid to the bath solution. This suggests that the effect of CO needs free radical production into the Xenopus oocytes. In parallel experiments, oocytes expressing Cx46 were exposed to the lipid peroxide 4-HNE (100 μM), and an evident hemichannel current inhibition was observed. n = 3 for each condition. (B) Representative recordings of oocytes expressing Cx46 placed in a DCFS, without (control) or with 100 μM CORM-2 (n = 3).
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