MECHANISMS OF EXOCYTOSIS Apical Plasma Membrane Traffic in Superficial Cells of Bladder Urothelium Mateja Erdani Kreft, a Kristijan Jezernik, a Marko Kreft, b,c and Rok Romih a a Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia b Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia c Celica Biomedical Center, Ljubljana, Slovenia Superficial urothelial cells that line the urinary bladder accommodate cyclical changes in organ volume while maintaining a permeability barrier between urine and tissue flu- ids. The specific apical plasma membrane traffic is necessary for their proper function. The composition of the apical plasma membrane is dramatically modified during dif- ferentiation of bladder urothelial cells, most notably by assembly of urothelial plaques containing uroplakins. However, the assembly of uroplakins into plaques, their inser- tion and removal from the apical surface, and the regulation of these processes are still poorly understood. This review examines the traffic (exocytosis/endocytosis) of the apical plasma membrane during differentiation of urothelial cells and focuses on the physiological and clinical significance of the apical plasma membrane traffic in bladder superficial urothelial cells. Key words: exocytosis; endocytosis; urothelium; differentiation; bladder pathology Introduction The urothelium, which is a pseudostratified epithelium composed of basal, intermediate, and superficial cells, lines the urinary tract from the renal pelvis to the proximal urethra 1 (Fig. 1). It is constantly flushed by urine, of which ionic strength, osmolality, and solute content changes considerably. Therefore urothelium forms a tight permeability barrier that prevents the un- regulated movements of water, ions, solutes, and toxic metabolites between urine and blood. In the urinary bladder this barrier must be maintained during cycles of bladder distension as it fills with urine and contraction caused by micturition. During distension–contraction cy- cles, superficial urothelial cells (SUCs) undergo Address for correspondence: Mateja Erdani Kreft, Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Lipiˇ ceva 2, SI-1000 Ljubljana, Slovenia. Voice: +386 1 543 7693; fax: +386 1 543 7681. mateja.erdani@mf.uni-lj.si transitions from a flattened to a cubical shape. Highly differentiated SUCs are also called um- brella or facet cells. The barrier function of the urothelium de- pends on the high resistance tight junctions be- tween SUCs and on the unique apical plasma membrane of SUCs. Between 70% and 90% of the apical plasma membrane of SUCs is cov- ered by rigid-looking plaques, that is, urothe- lial plaques. Between plaques there are regions of unthickened symmetrical membrane called hinge regions where otherwise rigid membranes can fold. Urothelial plaques contain a group of transmembrane proteins, uroplakins, which are expressed almost exclusively in the urothe- lium 2–6 (Fig. 1). Uroplakins Ia (27 kDa) and Ib (28 kDa) belong to tetraspanins, which play various roles in cell migration, cell signaling, vi- ral infections, and membrane architecture. 7–12 Uroplakin Ia is a urothelial receptor for binding uropathogenic Escherichia coli (UPEC), which represents more than 90% of the urinary tract Mechanisms of Exocytosis: Ann. N.Y. Acad. Sci. 1152: 18–29 (2009). doi: 10.1111/j.1749-6632.2008.04004.x C  2009 New York Academy of Sciences. 18