Byline: Monica. Acosta, Mohd. Mat Nor, Cindy. Guo, Odunayo. Mugisho, Frazer. Coutinho, Ilva. Rupenthal, Colin. Green
Compounds that block the function of connexin and pannexin protein channels have been suggested to be valuable therapeutics for a range of diseases. Some of these compounds are now in clinical trials, but for many of them, the literature is inconclusive about the molecular effect on the tissue, despite evidence of functional recovery. Blocking the different channel types has distinct physiological and pathological implications and this review describes current knowledge of connexin and pannexin protein channels, their function as channels and possible mechanisms of the channel block effect for the latest therapeutic compounds. We summarize the evidence implicating pannexins and connexins in disease, considering their homeostatic versus pathological roles, their contribution to excesive ATP release linked to disease onset and progression.
Connexin proteins form cell-to-cell gap junction channels for intercellular communication and signaling, but also cytoplasmic membrane pores called hemichannels, with both channel types emerging as key therapeutic targets for diverse diseases including cancer, retinopathies, neurodegenerative diseases and skin wounds (Vicario et al., 2017; Mugisho et al., 2019). Connexin protein channels contribute to the maintenance of cell integrity, and the coordination in space and time of vital communication signals. Pannexin proteins also form membrane channels of biological importance, and although generally agreed that they do not form cell-to-cell channels, recent reports show pannexins may in some circumstances form intercellular channels. Targeting pannexin and connexin protein channels and blocking the function of the pores they form minimizes the signaling burden of the biological process in which they participate. However, there are distinct differences between connexin hemichannel pores and gap junction channels, especially with regard to the action and roles of connexin and pannexin channels with important long-term consequences when blocking any one of these three distinct channel types. For example, both pannexins and connexins form ATP-release channels for paracrine signaling but pannexin channels are vital for cell homeostasis and long-term blockage of these pores causes dysregulated inflammation (Chen et al., 2019). On the contrary, connexin pores are transiently active in response to injury and are quite distinct from pannexin or gap junction channels through being formed and opening under human relevant pathological conditions (Bernstein and Fishman, 2016). There is vast literature of the therapeutic benefit of blocking hemichannels in pathological conditions and in this review, we address some of the more important features of pannexin and connexin channels that assist interpretation of the true mode of action of current anti-connexin therapeutics.
A systematic review of articles published from January 2000 through December 2019 was conducted using terms such as gap junction, connexin, pannexin, tonabersat, probenecid using the PubMed database. A few selected seminal publications expanding 1981-1998 were used to substantiate key statements. The final version of the review includes citations recommended by reviewers. Many important recent as well as seminal articles were not included in this review but have been cited by Leybaert et al. (2017).
An Overview of Connexins
The amino acid sequence...