Transmembrane transporters in health and disease

Transporters play a pivotal role in the translocation of molecules across biological membranes. Almost 400 different families of transport systems exist, which determine the fate of a plethora of different substrates. Accordingly, transporters regulate essentially all fundamental biological processes, including metabolism and energy supply, cytoplasmic concentrations of physiologically important ions, signal transduction and defense against potentially toxic agents. Transporter biology has attracted a steadily increasing interest and it is among the most rapidly growing fields. There are several reasons for this surge in popularity, not the least of which are that insights are of clinical relevance and that increased mechanistic understanding translates into therapeutic benefit (e.g. selective antidepressant drugs, psychostimulant therapy of attention-deficit hyperactivity disorder (ADHD), resistance to chemotherapy, drug-resistant epilepsy and many more). This consortium focuses on two medically relevant transport systems, neurotransmitter transporters and ABC- transporters and proposes to address three areas of enquiry: (i) study the structure-function relationship of these transporters and bacterial homologues thereof (suitable for structural approaches) by employing computational approaches (QSAR and pharmacophore modelling, computational structural biology), biochemical and biophysical techniques including atomic force microscopy, crystallography, electrophysiology, fluorescence correlation spectroscopy and related techniques. (ii) analyze by using cell biology, biochemistry and mouse genetics how expression of transporters is regulated by physiological stimuli, by the action of pharmacochaperones and by regulated export from the ER. (iii) translate these insights into clinical paradigms by developing PET-ligands to study drug-resistant epilepsy by correlating clinical data with transporter expression (NaPi-, serotonin-, dopamine transporters, P-glycoprotein) to understand the pathophysiology of variations in transporter expression and function; identify genetic polymorphisms accounting for phenotypic differences in drug response and disease susceptibility. The current consortium has been assembled under the assumption that there are several Austrian research groups whose interests are aligned under this common theme. We anticipate that this consortium has both, a critical mass and a unique combination of conceptual and technical know-how, to occupy a unique position, because we cover the range from bacteria to man, from structural analysis to understanding complex disease entities, from visualizing single molecules to functional imaging of transporters in the most complex tissue, the living brain. We thus bridge the gap between basic biology and clinical medicine. It is evident that the flow of information is not unidirectional in this consortium; disease-susceptibility or drug resistance may result from transporter gene polymorphisms and these may be identified in selected patients. Mechanistic insights on the effect of the mutation, however, require an understanding on how this alteration affects transporter structure, function and surface expression.