Invited Speaker

Cardiac Gap Junctions as Targets for Antiarrhythmic Therapy
Mario Delmar
USA

In the heart, electrical synchrony is achieved by the passage of ions and molecules between cells via intercellular channels called "gap junctions." These channels are formed by oligomerization of a protein called Connexin. In the heart, the most abundant connexin isotype is the 43 kDa protein Connexin43 (Cx43). Closure of gap junction channels has been associated with an increased propensity toward malignant cardiac arrhythmias and sudden death. Yet, a pharmacology of gap junctions is only a nascent field. Previous studies have identified molecules that enhance intercellular communication, and may offer potential for innovative antiarrhythmic therapy. However, their specific molecular target(s) and mechanism(s) of action remain unknown. Our group recently identified a 34-amino acid peptide (RXP-E) that binds the carboxyl terminal domain of Cx43 (Cx43CT) and prevents cardiac gap junction closure and action potential propagation block. These results supported the feasibility of a peptide-based pharmacology to Cx43, but the structure of the core active element in RXP-E, an essential step for pharmacological development, remained undefined. Here, we used a combination of molecular modeling, surface plasmon resonance, nuclear magnetic resonance and patch clamp strategies to define, for the first time, a unique ensemble of pharmacophores that bind Cx43CT and prevent closure of Cx43 channels. Two particular molecules are best representatives of this family: a cyclized heptapeptide (called CyRP-71), and a linear octapeptide of sequence RRNYRRNY. These two small compounds offer the first structural platform for the design of Cx43-interacting gap junction openers. Moreover, the structure of these compounds offers an imprint of a region of Cx43CT that is fundamental to gap junction channel function.