Pannexin and Connexin Signaling in Cell Death and Tissue Health and Disease

Since the seminal observation of Loewenstein and Kanno, it took almost 30 years to causally link connexin gene mutations to a human disease (in X-linked Charcot-Marie-Tooth disease) outside the cancer field (Bergoffen et al., 1993). This finding was unexpected, as the particular connexin, Connexin32 (Cx32), which was thought to be an epithelial-specific connexin, was identified in Schwann cells with a critical role in myelin maintenance. This work inspired the description of many more connexin-related genetic diseases, growing over 20 years, with the parallel discovery of new connexin isoforms, establishing connexins as members of a multigene family. Connexin mutations are now known to cause a wide range of genetic diseases affecting hearing (cochlea), skin keratinization, heart function, lens transparency, etc (Srinivas et al., 2018). Many of these discoveries were confirmed by the increased use of transgenic strategies in mice permitting visualization of the pathophysiological effects of modulating connexin expression.In parallel, investigations of connexin function and biology showed that at least some connexins could not only mediate direct intercellular communication through gap junctions, but also communicate between intracellular and extracellular domains through unopposed connexin channels (connexons) in the plasma membrane. This so-called hemichannel activity is associated with pathological events (ischemia, Ca 2+ concentration modulation, inflammation, etc.). Subsequently, another family of large pore transmembrane proteins, the pannexins, was identified as the vertebrate homologs of innexins, gap junction proteins in invertebrates. It is now well established that pannexins indeed share similar functions with connexin hemichannels, particularly in cell death and inflammation by permitting the release of pro-inflammatory molecules (Makarenkova et al., 2018), but are unlikely to form gap junctions.Our understanding of the involvement of connexins and pannexins in human health has rapidly expanded since 1966. This diversity appears in the seven articles gathered in this special issue. In this collection, the implication of these proteins in the inflammatory cell response is largely presented in three reviews, with one extending to other large pore channels (innexins, calcium homeostasis modulator, and leucine-rich repeat-containing 8 proteins) including pannexin channels and connexin hemichannels (Vega et al., Apart from these four review articles, the 3 original articles of this special issue focus on 3 different connexins in various tissues. One of these connexins, the ortholog of human Cx36 (Cx35.1, abundant in electrical synapses) in zebra fish, is seen to be important for visual effects and related behavior, since its depletion causes hyperopia and visual-motor deficiencies (Brown-Panton et al., https://www.frontiersin.org/articles/10.3389/fcell.2023.1150273/full). Another article describes the consequences of Cx30.3 mutations affecting trafficking towards the plasma membrane, implicated in the rare skin disorder Erythrokeratodermia Variabilis et Progressiva (EKVP). Interestingly, as up to nine different types of connexins can be co-expressed in keratinocytes, this study shows that expression of other connexins permits transdominant rescue of Cx30.3, which can then be targeted to the plasma membrane. Such an astonishing effect is seen as a possible therapeutic strategy that should be investigated (Lucaciu et al., https://www.frontiersin.org/articles/10.3389/fcell.2023.1073805/full). The involvement of a third connexin (Cx26) in another skin disorder associated with hearing loss (Keratitis Ichthyosis Deafness syndrome) was explored through a mutation exhibiting hyperactive hemichannel activity in the supporting cells of the organ of Corti in the cochlea. By using appropriate in vivo and in vitro models, the authors deduce hyperactive Cx26 hemichannels induce cell damage by permitting Ca 2+ influx, leading to hair (stereocilia) loss and subsequent deafness (Abbott et al., https://www.frontiersin.org/articles/10.3389/fcell.2022.1071202/full).As we can see, the seven articles (4 reviews and 3 original research articles) in this issue show the complexity of pannexin and connexin involvement in tissue health and disease. While decades ago defective gap junctions were thought to be solely responsible for connexin-related human diseases, it now appears to frequently be a consequence of uncontrolled pannexin or connexin-mediated communication between the intracellular and extracellular space. A better understanding of the molecular mechanisms involved may permit connexins and pannexins to be targets for possible new therapeutic strategies.