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Therapeutic strategies targeting connexins

Abstract

The connexin family of channel-forming proteins is present in every tissue type in the human anatomy. Connexins are best known for forming clustered intercellular channels, structurally known as gap junctions, where they serve to exchange members of the metabolome between adjacent cells. In their single-membrane hemichannel form, connexins can act as conduits for the passage of small molecules in autocrine and paracrine signalling. Here, we review the roles of connexins in health and disease, focusing on the potential of connexins as therapeutic targets in acquired and inherited diseases as well as wound repair, while highlighting the associated clinical challenges.

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Figure 1: Connexin topology and the connexin family.
Figure 2: Canonical life cycle of connexins.
Figure 3: Links between connexins, the connexin interactome and early-stage tumorigenesis.
Figure 4: Current and potential connexin-modulating therapeutic strategies.

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Acknowledgements

Given the >20,000 reports on connexins and pannexins and reference number limitations, the authors apologize for not including many primary articles and for summarizing many exciting findings by citing reviews. Work in the authors' laboratories is supported by a US National Institutes of Health grant (GM55632) to P.D.L. and the Canadian Institutes of Health Research (130530, 123228, 148630 and 148584) and Canada Research Chair Program to D.W.L.

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Correspondence to Dale W. Laird.

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P.D.L. is a non-paid member of the scientific advisory board of FirstString Research and has been granted stock options (currently no value) for his service. D.W.L. received a small 1-year grant from Zealand Pharma in 2016 to test potential pannexin 1-modulating peptides.

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Glossary

Connexins

Tetraspanning membrane proteins that are the molecular constituent of gap junctions.

Hemichannel

A connexon that has the ability to open for the passage of small molecules.

Ischaemia–reperfusion injury

(IRI). An injury that occurs when blood supply (oxygen) returns to tissue after a period of ischaemia (hypoxia). Damage following oxygen restoration results in inflammation and oxidative damage.

Connexon

A hexamer arrangement of connexins that contains the same or different connexin proteins arranged into an oligomer.

Gap junctional intercellular communication

(GJIC). The process in which contacting cells harbouring functional gap junctions exchange small molecules.

Perinexus

A zone at the periphery of gap junctions that is enriched in connexons and hemichannels, at which Cx43–zonula occludens 1 interactions can occur.

Connexosomes

Double-membraned structures formed from the internalization of gap junction components from contacting cells.

Intercalated discs

Specialized membrane structures at the ends of cardiomyocytes that contain desmosomes, adherens junctions, sodium channels and gap junctions and allow depolarization waves to transmit from one cell to its neighbour.

Peptide mimetics

Short peptide sequences of usually 8–24 amino acids that correspond to segments of connexin proteins that can be used to modulate connexin function.

Antisense oligodeoxynucleotide

(AsODN). A short-chain nucleotide that can be designed to target connexin-encoding RNA to block protein expression.

Zonula occludens 1

(ZO1). ZO1 is a membrane-associated guanylate kinase (MAGUK) scaffolding protein that interacts with Cx43 and tight junction-associated proteins.

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Laird, D., Lampe, P. Therapeutic strategies targeting connexins. Nat Rev Drug Discov 17, 905–921 (2018). https://doi.org/10.1038/nrd.2018.138

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