Therapeutic Targeting of Connexin Channels: New Views and Challenges

The biggest challenge is to know how Cx-mimetic peptides execute their blocking/enhancing effects at the molecular level. Different domains on the CT of Cx43 were characterized to be involved in loop/tail interactions, and open perspectives for the development of new Cx-mimetic peptides. The possibility of establishing a knockout or mutant knock-in mouse model specifically for modulation of either Cx43 HC or GJC functions recently led to new strategies to discriminate HCs and GJCs in a tissue-specific manner. Distinct pathological conditions display the presence of leaky HCs, and their blockade proved to be advantageous. Next to reducing the cardiac infarct size after ischemia/reperfusion, blocking Cx43 HCs also led to a significant improvement in vascular recovery in human ocular epithelial defects, highlighting the potential of the use of Cx-mimetic peptides in a preclinical setting. Connexins, in particular connexin 43 (Cx43), function as gap junction channels (GJCs) and hemichannels (HCs). Only recently, specific tools have been developed to study their pleiotropic functions. Based on various protein interaction sites, distinct connexin-mimetic peptides have been established that enable discrimination between the function of HCs and GJCs. Although the precise mechanism of action of most of these peptides is still a matter of debate, an increasing number of studies report on important effects of those compounds in disease models. In this review, we summarize the structure, life cycle, and the most important physiological and pathological functions of both connexin GJCs and HCs. We provide a critical overview on the use of connexin-targeting peptides, in particular targeting Cx43, with a special focus on the remaining questions and hurdles to be taken in the research field of connexin channels. Connexins, in particular connexin 43 (Cx43), function as gap junction channels (GJCs) and hemichannels (HCs). Only recently, specific tools have been developed to study their pleiotropic functions. Based on various protein interaction sites, distinct connexin-mimetic peptides have been established that enable discrimination between the function of HCs and GJCs. Although the precise mechanism of action of most of these peptides is still a matter of debate, an increasing number of studies report on important effects of those compounds in disease models. In this review, we summarize the structure, life cycle, and the most important physiological and pathological functions of both connexin GJCs and HCs. We provide a critical overview on the use of connexin-targeting peptides, in particular targeting Cx43, with a special focus on the remaining questions and hurdles to be taken in the research field of connexin channels. synonym for 'connexosome'; a double-membrane structure formed by the internalization of (fragments of) gap junctional plaques into one of the cells that share the gap junction. a type of cell signaling in which a cell produces and secrets chemical agents that bind on receptors of that same cell, thereby inducing changes in this cell. human diseases characterized by mutations in one or more connexin genes, with altered channel or nonchannel function. synonym for 'annular junction'; a double-membrane structure formed by the internalization of (fragments of) gap junctional plaques into one of the cells sharing the gap junction. a chemical agent released by glial cells, that contributes to synaptic signaling between neurons. Molecules that easily dissolve in water or other watery solvents. a form of cell–cell communication that requires close contact between two cells involving protein–protein interactions. small peptides identical to defined sequences on the connexin protein, aiming to interfere with channel or nonchannel connexin functions. a type of cell–cell communication where secreted chemical agents from one cell reach nearby located cells, in which they induce a new cellular response. the description of molecular features that are needed for a ligand (a connexin protein domain, a peptide, or others) to be recognized by a target site on a protein. a region in the plasma membrane where thousands of gap junctional channels are densely packed together. Src homology domain 3 located on the C-terminal tail of connexin43, with which c-Src interacts. a powerful technique used to investigate in vitro interactions between proteins or peptides.