BBB seminar: Jens Waschke

Jens Waschke
Institute of Anatomy and Cell Biology, Ludwig-Maximilians-University Munich, Germany

Adherens junctions (AJ) and desmosomes are the major adhesive contacts providing mechanical strength to endothelial/epithelial cell cohesion and barrier function. Both consist of cadherin family adhesion molecules. In endothelial cells VE-cadherin in AJ is crucial for endothelial barrier function. Inflammatory mediators in sepsis which increase permeability, impair VE-cadherin-mediated adhesion and barrier properties at least in part via a signaling pathway leading to reduced cAMP-mediated Rac1 activation. Our recent data show that cAMP-activated protein kinase (PKA) forms a complex with AJ and indicate that compartmentalization of cAMP signaling via A-kinase anchoring proteins (AKAPs) is crucial for barrier regulation. In desmosomes of keratinocytes, desmogleins (Dsg) and desmocollins are the cadherin-type adhesion molecules. Since Dsg1 and Dsg3 are the major antigens targeted by autoantibodies from patients suffering from the autoimmune blistering skin disease pemphigus, these antibodies can be utilized to investigate the mechanisms regulating desmosomal adhesion. From these studies we learned that Dsg3, besides it adhesive properties, has isoform-specific signaling functions, for example, by forming an adhesive signaling contact containing p38 mitogen-activated protein kinase (p38MAPK). We started now to characterize more complex junctions where desmosomes and AJ are combined with tight junctions and gap junctions such as the junctional complex of intestinal epithelium or intercalated discs of cardiomycytes. Novel data show that Dsg2 in enterocytes is important for intestinal barrier integrity and may play a role in the pathogenesis of Crohn’s disease. In cardiomyocytes where Dsg2 mutations can cause arrythmogenic cardiomyopathy we observed that impaired Dsg2 binding affects cardiomyocyte function in isolated hearts. Interestingly, cAMP appears to regulate Dsg2 in intercalated discs which also harbor the β-adrenergic receptor.

Chairperson: Rolf K. Reed <rolf.reed@biomed.uib.no>, Department of Biomedicine