International Journal of Molecular Sciences

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Dear Colleagues,

Gap junctions play a critical role in a plethora of physiological processes by facilitating direct intercellular communication. They are composed of two hemichannels of neighbouring cells, which in turn are built up by six connexin proteins. Over the past two decades, it has become clear that connexin hemichannels can also provide a pathway for cellular communication on their own, albeit between the cytosol of an individual cell and its extracellular environment. Furthermore, a novel class of connexin-like proteins was identified 20 years ago, namely, pannexins, which gather at the cell plasma membrane surface in a configuration reminiscent of connexin hemichannels. Unlike gap junctions, connexin hemichannels and pannexin channels seem to become active predominantly under pathological conditions by supporting inflammation and cell death.

This Special Issue of the International Journal of Molecular Sciences focuses on the connexin and pannexin research field, and welcomes both original research articles and review papers that deal with the molecular mechanisms underlying the role of connexin and pannexin signaling in health and disease.

Prof. Dr. Mathieu Vinken
Guest Editor

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Keywords

connexin
pannexin
hemichannel
gap junction
physiology
pathology
mechanisms

Published Papers (1 paper)

Research

19 pages, 8385 KiB

Open AccessArticle

Orally Delivered Connexin43 Hemichannel Blocker, Tonabersat, Inhibits Vascular Breakdown and Inflammasome Activation in a Mouse Model of Diabetic Retinopathy

by Odunayo O. Mugisho, Jyoti Aryal, Avik Shome, Heather Lyon, Monica L. Acosta, Colin R. Green and Ilva D. Rupenthal

Int. J. Mol. Sci. 2023, 24(4), 3876; https://doi.org/10.3390/ijms24043876 - 15 Feb 2023

Cited by 5 | Viewed by 1839

Abstract

Diabetic retinopathy (DR), a microvascular complication of diabetes, is associated with pronounced inflammation arising from the activation of a nucleotide-binding and oligomerization domain-like receptor (NLR) protein 3 (NLRP3) inflammasome. Cell culture models have shown that a connexin43 hemichannel blocker can prevent inflammasome activation in DR. The aim of this study was to evaluate the ocular safety and efficacy of tonabersat, an orally bioavailable connexin43 hemichannel blocker, to protect against DR signs in an inflammatory non-obese diabetic (NOD) DR mouse model. For retina safety studies, tonabersat was applied to retinal pigment epithelial (ARPE-19) cells or given orally to control NOD mice in the absence of any other stimuli. For efficacy studies, either tonabersat or a vehicle was given orally to the inflammatory NOD mouse model two hours before an intravitreal injection of pro-inflammatory cytokines, interleukin-1 beta, and tumour necrosis factor-alpha. Fundus and optical coherence tomography images were acquired at the baseline as well as at 2- and 7-day timepoints to assess microvascular abnormalities and sub-retinal fluid accumulation. Retinal inflammation and inflammasome activation were also assessed using immunohistochemistry. Tonabersat did not have any effect on ARPE-19 cells or control NOD mouse retinas in the absence of other stimuli. However, the tonabersat treatment in the inflammatory NOD mice significantly reduced macrovascular abnormalities, hyperreflective foci, sub-retinal fluid accumulation, vascular leak, inflammation, and inflammasome activation. These findings suggest that tonabersat may be a safe and effective treatment for DR. Full article

(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease 3.0)

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