Gap junctions are groups of transmembrane channels that connect the cytoplasms of adjacent cells to mediate the diffusion of small molecules, such as ions, metabolites, second messengers and small peptides. The building blocks of gap junctions are connexin proteins. The most ubiquitous and best studied connexin is connexin43 (Cx43). Cx43 is also known as the heart connexin. In the heart, gap junctional communication between cardiomyocytes ensures efficient electrical coupling and hence the synchronous propagation of action potentials. Misregulation of Cx43 expression, localisation and channel gating may lead to severe cardiac dysfunction. Cx43-based cell-cell coupling is rapidly disrupted following stimulation of certain G protein-coupled receptors (GPCRs). The studies presented in this thesis focus on the quest to unravel the signalling pathways leading to the transient inhibition of Cx43-based communication by GPCR activation. Our results suggest a model in which GPCR agonists inhibit Cx43-based gap junctional communication in two phases. Initial closure of the Cx43 channels si mediated by depletion of the phospholipid PIP2 from the plasma membrane, followed by internalisation of the gap junctions due to ubiquitination of Cx43 by the ubiquitin ligase Nedd4. New insights into the mechanisms underlying Cx43 gap junction closure may lead to new treatments of heart failure.KWF CBGUBL - phd migration 201
