BBB seminar: Michael Caplan
Trafficking of ion transport proteins: new partners and potential therapies
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
The physiologic function of an ion transport protein is determined, in part, by its sub-cellular localization and by the cellular mechanisms that modulate its activity. We are interested in the molecular signals and interactions that control the sorting and regulation of ion transport proteins in polarized cells. We have recently found that members of the tetraspan family of membrane proteins interact with a wide variety of ion transport systems. Through direct associations, members of this family appear to play very significant roles in determining the subcellular distributions and dynamic properties of a number of different transport systems. Several transport related diseases result from mis-trafficking of ion transport proteins. Cystic fibrosis is one of these trafficking diseases. Most cases result from mutations in the cystic fibrosis transmembrane regulator (CFTR) chloride channel that cause this protein to be retained in the endoplasmic reticulum (ER). We have identified a new small molecule approach to liberate mutant CFTR protein from the ER such that it can achieve at least partial function at the cell surface. This compound is non-toxic and appears to be effective in mouse models of cystic fibrosis. The compound appears to exert its effects by altering the interaction of CFTR with the chaperone proteins that retain it within the cell.
|Michael Caplan studied at Harvard and Yale Universities and obtained his M.D. Ph.D. degree from the latter in 1987. His main research interest concerns protein sorting in polarised cells, with emphasis on trafficking of ion transport proteins. Two years ago his group reported that the Ca2+-ATPase inhibitor thapsigargin abolishes the effect of the F508 deletion in the cystic fibrosis transmembrane regulator (CFTR), that causes the mutant protein to be retained in the endoplasmic reticulum (ER), resulting in functional expression of the protein at the surface of epithelial cells (Egan et al., Nature Medicine, May 2002, vol. 8, pp. 485-492). The finding of the small molecule approach to release CFTR from the ER, which Michael Caplan will discuss in his lecture, has been accepted for publication in Science.|