Differential Action of Connexin Hemichannel and Pannexin Channel Therapeutics for Potential Treatment of Retinal Diseases.

Mohd N Mat Nor,Monica L Acosta,Ilva D Rupenthal,Colin R Green

doi:10.3390/ijms22041755

Mohd N Mat Nor, Monica L Acosta + Show 2 more

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https://doi.org/10.3390/ijms22041755

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Abstract

Dysregulation of retinal function in the early stages of light-induced retinal degeneration involves pannexins and connexins. These two types of proteins may contribute to channels that release ATP, leading to activation of the inflammasome pathway, spread of inflammation and retinal dysfunction. However, the effect of pannexin channel block alone or block of both pannexin channels and connexin hemichannels in parallel on retinal activity in vivo is unknown. In this study, the pannexin channel blocker probenecid and the connexin hemichannel blocker tonabersat were used in the light-damaged rat retina. Retinal function was evaluated using electroretinography (ERG), retinal structure was analyzed using optical coherence tomography (OCT) imaging and the tissue response to light-induced injury was assessed immunohistochemically with antibodies against glial fibrillary acidic protein (GFAP), Ionized calcium binding adaptor molecule 1 (Iba-1) and Connexin43 (Cx43). Probenecid did not further enhance the therapeutic effect of connexin hemichannel block in this model, but on its own improved activity of certain inner retina neurons. The therapeutic benefit of blocking connexin hemichannels was further evaluated by comparing these data against results from our previously published studies that also used the light-damaged rat retina model. The analysis showed that treatment with tonabersat alone was better than probenecid alone at restoring retinal function in the light-damaged retina model. The results assist in the interpretation of the differential action of connexin hemichannel and pannexin channel therapeutics for potential treatment of retinal diseases.

Highlights

We have shown that systemic delivery of tonabersat alone significantly improved retinal function assessed by ERG 1 week after treatment, and was significantly better again at 2 weeks post treatment [15]
We previously have shown that oral tonabersat (10–90 μM) delivered during light damage significantly improved function at 1 week, 2 weeks and 3 months post-treatment [13] compared to retinas from vehicle-only treated animals
The present study was conducted to evaluate the therapeutic effect of connexin hemichannel and pannexin channel modulators, tonabersat and probenecid, respectively, in the rat bright light-damaged retina model, a model that mimics aspects of inflammation in degenerative retinal disease. in general, the results suggest that there is a strong association between functional and structural recovery of the light-damaged retina when treated with probenecid alone and in combination with tonabersat but with significant differences in functional recovery by retinal cell type

Summary

Introduction

Two large membrane pores have been proposed to play a role in response to injury or disease—the connexin hemichannel and the pannexin channel. A connexin hemichannel (or connexon) is comprised of six connexin subunits, with two connexons from adjacent cells docking together to form a gap junction channel linking the cytoplasm of the two cells. Most organs express different types of connexins and form heterotypic or homotypic gap junction channels. In contrast to the gap junction, opening of Cx43 undocked hemichannels implicates injury, extracellular cell signaling and a mechanical stimulation response in various tissues [3,4]. Hemichannels need to remain primarily closed or they form a large, non-specific membrane pore exposing the cell cytoplasm to the extracellular milieu [5]. The opening of connexin hemichannels is the result of molecular and physical insults that disrupt normal homeostasis [4,5,6]

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