Tissue homeostasis is driven by a myriad of extracellular, intracellular and intercellular signaling networks. Direct communication between neighboring cells is typically controlled by gap junctions. Gap junctions mediate the intercellular diffusion of small and hydrophilic substances, mainly homeostasis regulators. This flux is denoted gap junctional intercellular communication (GJIC) and is considered as a key mechanism in the maintenance of tissue functioning. Over the last decades, GJIC has been shown indispensable for the establishment of metabolic or electrical intercellular coupling in all vital organs, such as the liver. Gap junctions are formed by the docking of 2 hemichannels of adjacent cells, which in turn are composed of 6 connexin proteins. At present, 21 different connexins have been identified in humans, all which are expressed in a cell-specific way and that are named based upon their molecular weight. Connexin proteins share a common molecular structure consisting of 4 transmembrane domains, 2 extracellular loops, 1 cytosolic loop, 1 cytosolic aminotail and 1 cytosolic carboxytail (Figure 1).
Although considered as merely structural precursors of gap junctions for a long time, an abundance of reports published in the last few years shows that connexin hemichannels as such can provide a pathway for cellular communication, albeit between the cytosol of individual cells and their extracellular environment and not between adjacent cells as is the case for GJIC. Nonetheless, the messengers that are conveyed through connexin hemichannels are very similar to those involved in GJIC. Furthermore, connexin hemichannels are regulated by mechanisms that equally affect gap junctions, yet an identical factor can have opposing effects on the 2 channels types, such as shown for certain inflammatory triggers. In line with this notion, connexin hemichannels, unlike their full channel counterparts, display a low open probability. In fact, connexin hemichannels seem to be preferably activated by pathological stimuli, including ischemia-reperfusion insults and oxidative stress, and thereby drive processes like cell death and inflammation. For this very reason, connexin hemichannels are sometimes considered as “pathological pores”. To make the picture even more complicated, a novel class of connexin-like proteins has been introduced in the last few years, namely the pannexin that gather in a hemichannel configuration. They also facilitate extracellular communication and fulfil both physiological and pathological functions (Figure 1).
The connexin research field has been surrounded by a lot of controversy in the last few years. Specifically, the concept of (dys)functional connexin hemichannels has been debated heavily on several occasions. A major reason for this impediment is the ubiquitous lack of tools and technologies to distinguish between the different channel types, in casu between gap junctions and connexin hemichannels.
Classical strategies, such as the use of RNA interference-based technologies, genetically modified animals or even antibodies, are indeed not applicable, as they target connexins, which are the shared building stones of gap junctions and connexin hemichannels. Furthermore, most, if not all, of the routinely used gap junction inhibitors, including long-chain alcohol substances, anaesthetic substances, the glycyrrhetinic acid derivative carbenoxolone and the fenamate family of blockers, equally suppress connexin hemichannel activity. Great expectations now lie with peptides that reproduce sequences in the cytosolic loop regions of connexins, as they suppress connexin hemichannel activity without influencing GJIC. In a similar way, pannexin mimetic peptides are also known to shut down pannexin channels. This area is still in its infancy and defines the area of expertise of our group. We are developing new specific connexin hemichannel and pannexin channel inhibitors. They can be potentially used for a plethora of clinical purposes, especially for the treatment of disease associated with cell death and inflammation. Although our primary focus is put on liver disease, including acute liver failure, liver fibrosis and steatosis, these compounds are very promising for a number of other (life-threatening) pathologies. We are continuously looking for partners to elaborate this research.
Interested parties can contact: