The mutual interplay of redox signaling and connexins

Zhang, Kai; Guan, Qi-Wen; Zhou, Xinyu; Xia, Qin-Xuan; Yin, Xi-Xi; Zhou, Hong‐Hao; Mao, Xiao‐Yuan

doi:10.1007/s00109-021-02084-0

Cited by 8 publications

(4 citation statements)

References 72 publications

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“…An association between connexins, redox potential and oxidative stress is well established ( Quan et al, 2021 ; Zhang et al, 2021 ), although low or physiological levels NO could have a protective effect in lens epithelial cells ( Chamberlain et al, 2008 ). A high production of NO in human lens has been associated with cataracts, especially in hypertensive patients ( Ornek et al, 2003 ) and smokers ( Anitha et al, 2019 ), and a similar association has been found in animal models of hypertension and diabetes ( Abdul Nasir et al, 2017 ; Yadav et al, 2018 ).…”

Section: Cx46 Posttranslational Modifications and Their Potential Rel...mentioning

confidence: 99%

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

Retamal

Altenberg

2022

Front. Physiol.

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Connexins are a family of proteins that can form two distinct types of channels: hemichannels and gap junction channels. Hemichannels are composed of six connexin subunits and when open allow for exchanges between the cytoplasm and the extracellular milieu. Gap junction channels are formed by head-to-head docking of two hemichannels in series, each one from one of two adjacent cells. These channels allow for exchanges between the cytoplasms of contacting cells. The lens is a transparent structure located in the eye that focuses light on the retina. The transparency of the lens depends on its lack of blood irrigation and the absence of organelles in its cells. To survive such complex metabolic scenario, lens cells express Cx43, Cx46 and Cx50, three connexins isoforms that form hemichannels and gap junction channels that allow for metabolic cooperation between lens cells. This review focuses on the roles of Cx46 hemichannels and gap junction channels in the lens under physiological conditions and in the formation of cataracts, with emphasis on the modulation by posttranslational modifications.

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Section: Cx46 Posttranslational Modifications and Their Potential Rel...mentioning

confidence: 99%

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

Retamal

Altenberg

2022

Front. Physiol.

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“…These cysteines are not susceptible to posttranslational modification, namely to S-nitrosylation, and what is worth noting, there is an assumption that these cysteines are not responsible for docking solely, but may also act as extracellular redox sensors [36]. The recent review discusses the interplay of redox signaling and Cnxs in normal and pathological conditions [37]. Also, point mutations artificially induced in extracellular loops led to failed docking yet did not affect Cnx43 tumor suppressive properties thus confirming strong Cnx43 non-channel functions [38].…”

Section: Connexin Protein Structure and Its Relation To Cancer Progre...mentioning

confidence: 99%

The Multifaceted Role of Connexins in Tumor Microenvironment Initiation and Maintaining

Kutova¹,

Pospelov²,

Balalaeva³

2021

Preprint

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The modern paradigm of studying the processes of carcinogenesis and vital activity of tumor tissues implies increased attention to constituents of tumor microenvironment (TME) and their interactions. These interactions between the cells in TME can be mediated via protein junctions of different types. Connexins (Cnxs) are one of the major contributors to intercellular communication. They form gap junctions responsible for the transfer of ions, metabolites, peptides, miRNA, etc. between neighboring tumor cells as well as between tumor and stromal cells. Cnx hemichannels mediate purinergic signaling and bidirectional molecular transport with the extracellular environment. Additionally, Cnxs were reported to localize in tumor-derived exosomes and facilitate the release of their cargo. A large body of evidence implies that the role of connexins in cancer is multifaceted. Pro- or anti-tumorigenic properties of connexins are determined by their abundance, localization and functionality as well as channel assembly and non-channel functions. In this review we have summarized the data on the Cnxs contribution in TME and to the cancer initiation and progression.

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“…There are 21 genes coding for different types of Cxs, but despite this heterogeneity, all Cxs share a common topology, including N- and C-termini located in the cytoplasmic side, four transmembrane domains (TM1-4), one intracellular loop (IL-1), and two extracellular loops (EL1-2) [ 8 , 9 ]. In all cases, the C-terminal is the most variable region and comprises several post-translational sites, which include sites for phosphorylation [ 10 , 11 , 12 ], redox- potential-mediated modifications [ 13 , 14 , 15 ], cleavage [ 16 ], and protein–protein interactions [ 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

KI04 an Aminoglycosides-Derived Molecule Acts as an Inhibitor of Human Connexin46 Hemichannels Expressed in HeLa Cells

et al. 2023

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Background: Connexins (Cxs) are proteins that help cells to communicate with the extracellular media and with the cytoplasm of neighboring cells. Despite their importance in several human physiological and pathological conditions, their pharmacology is very poor. In the last decade, some molecules derived from aminoglycosides have been developed as inhibitors of Cxs hemichannels. However, these studies have been performed in E. coli, which is a very simple model. Therefore, our main goal is to test whether these molecules have similar effects in mammalian cells. Methods: We transfected HeLa cells with the human Cx46tGFP and characterized the effect of a kanamycin-derived molecule (KI04) on Cx46 hemichannel activity by time-lapse recordings, changes in phosphorylation by Western blot, localization by epifluorescence, and possible binding sites by molecular dynamics (MD). Results: We observed that kanamycin and KI04 were the most potent inhibitors of Cx46 hemichannels among several aminoglycosides, presenting an IC50 close to 10 μM. The inhibitory effect was not associated with changes in Cx46 electrophoretic mobility or its intracellular localization. Interestingly, 5 mM DTT did not reverse KI04 inhibition, but the KI04 effect completely disappeared after washing out KI04 from the recording media. MD analysis revealed two putative binding sites of KI04 in the Cx46 hemichannel. Results: These results demonstrate that KI04 could be used as a Cx46 inhibitor and could help to develop future selective Cx46 inhibitors.

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The mutual interplay of redox signaling and connexins

Cited by 8 publications

References 72 publications

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

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

The Multifaceted Role of Connexins in Tumor Microenvironment Initiation and Maintaining

KI04 an Aminoglycosides-Derived Molecule Acts as an Inhibitor of Human Connexin46 Hemichannels Expressed in HeLa Cells

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