Connexin modulators and their potential targets under the magnifying glass

Gap junction channels, assembled from connexins, mediate communication and signaling between adjacent cells by allowing the passage of ions, metabolites and signaling molecules. Their physiological significance and importance in cellular homeostasis is reflected by the fact that their dysfunction leads to a multitude of pathologies. However, the complex physiological and pathophysiological roles of connexins are not well understood. Therefore, pharmacological tools to further elucidate their functions and to validate them as drug targets for the development of novel therapies for connexin-based diseases are urgently needed. In this article we will review diseases caused by mutations, abnormal expression and function of connexins (e.g. deafness, atrial fibrillation and other cardiac arrhythmias, peripheral and central nervous system neuropathies, epilepsy, and cancer) and we will discuss the role of connexins as potential therapeutic targets. This will be followed by a detailed overview of the different classes of modulators including proposed mechanisms of action, selectivity and structure-activity relationships. Classical connexin channel uncoupling agent like long-chain alcohols (e.g. heptanol), glycyrrhetinic acid and its derivatives, later discovered connexin blocking chemotypes like 2-aminophenoxyborates, fenamates, quinines and triphenylmethanes, as well as gap junctional coupling enhancing compounds like antiarrhythmic peptides will be discussed.