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The mutual interplay of redox signaling and connexins

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Abstract

Connexins (Cxs) are ubiquitous transmembrane proteins that possess both channel function (e.g., formations of gap junction and hemichannel) and non-channel properties (e.g., gene transcription and protein-protein interaction). Several factors have been identified to play a role in the regulation of Cxs, which include those acting intracellularly, as redox potential, pH, intramolecular interactions, and post-translational modifications (e.g., phosphorylation, S-nitrosylation) as well as those acting extracellularly, such as Ca2+ and Mg2+. The relationship between redox signaling and Cxs attracts considerable attention in recent years. There is ample evidence showing that redox signaling molecules (e.g., hydrogen peroxide (H2O2), nitric oxide (NO)) affect Cxs-based channel function while the opening of Cx channels also triggers the transfer of various redox-related metabolites (e.g., reactive oxygen species, glutathione, nicotinamide adenine dinucleotide, and NO). On the basis of these evidences, we propose the existence of redox-Cxs crosstalk. In this review, we briefly discuss the interaction between redox signaling and Cxs and the implications of the intersection in disease pathology and future therapeutic interventions.

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Abbreviations

BTF3:

Basic transcription factor-3

Cav-1:

Caveolin-1

CBX:

Carbenoxolone

Cx:

Connexin

Cys:

Cysteine

DTT:

Dithiothreitol

EL:

Extracellular loop

eNOS:

Endothelial nitric oxide synthase

GJ:

Gap junction

GSH:

Glutathione

GSNO:

S-nitrosoglutathione

H2O2 :

Hydrogen peroxide

HC:

Hemichannel

HM:

Hematopoietic microenvironment

HSCs:

Hematopoietic stem cells

HSC/P:

HSC and progenitor

IL:

Intracellular loop

IP3:

Inositol 1, 4, 5-trisphosphate

NAD+ :

Nicotinamide adenine dinucleotide

NADPH:

Nicotinamide adenine dinucleotide phosphate hydrogen

NO:

Nitric oxide

NOX2:

NADPH oxidase 2

OS:

Oxidative stress

PKG:

Protein kinase G

ROS:

Reactive oxygen species

SNO:

S-nitrosylation

TM:

Transmembrane domain

ZO-1:

Zonula occludens-1

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Funding

This work was financially supported by the National Natural Science Foundation of China (Nos. 81974502, 81671293, and 81302750), Natural Science Foundation of Hunan Province (No. 2020JJ3061), and Hunan Provincial Department of Education Innovation Platform Open Fund Project (No. 17K100).

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  1. Kai Zhang, Qi-Wen Guan and **n-Yu Zhou contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Pharmacology, **angya Hospital and Institute of Clinical Pharmacology, Central South University, 87 **angya Road, Changsha, 410008, People’s Republic of China

    Kai Zhang, Qi-Wen Guan, Qin-Xuan **a, Hong-Hao Zhou & **ao-Yuan Mao

  2. Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, 110 **angya Road, Changsha, 410078, People’s Republic of China

    Kai Zhang, Qi-Wen Guan, Qin-Xuan **a, Hong-Hao Zhou & **ao-Yuan Mao

  3. Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 **angya Road, Changsha, 410078, People’s Republic of China

    Kai Zhang, Qi-Wen Guan, Qin-Xuan **a, Hong-Hao Zhou & **ao-Yuan Mao

  4. National Clinical Research Center for Geriatric Disorders, 87 **angya Road, Changsha, 410008, Hunan, People’s Republic of China

    Kai Zhang, Qi-Wen Guan, Qin-Xuan **a, Hong-Hao Zhou & **ao-Yuan Mao

  5. Department of Neurology, Lianyungang Hospital affiliated with Xuzhou Medical College, Tongguan Road, 182, Lianyungang, Jiangsu, People’s Republic of China

    **n-Yu Zhou

  6. Department of Pediatrics, **angya Hospital, Central South University, 87 **angya Road, Changsha, 410008, Hunan, People’s Republic of China

    **-** Yin

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XYM designed and revised the manuscript. KZ, QWG, and XYZ wrote the manuscript. QXX, XXY, and HHZ contributed to literature arrangement and the generation of figures and tables. All authors read and approved the final version of manuscript.

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Correspondence to **ao-Yuan Mao.

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Zhang, K., Guan, QW., Zhou, XY. et al. The mutual interplay of redox signaling and connexins. J Mol Med 99, 933–941 (2021). https://doi.org/10.1007/s00109-021-02084-0

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