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My group is mainly interested in mammalian transport proteins of the plasma mebrane. We use heterologous expression of cloned transporter cDNAs in cultured cell lines to assay transporter function. We have been thoroughly involved in the discovery and characterization of the non-neuronal monoamine transporters OCT1, OCT2, and EMT. Our mission in general is to identify and develop among the transport proteins new drug targets. Many carriers are still undefined or ill-defined in terms of substrate specificity. Clearly, without knowledge of the physiological substrate(s), we can not possibly understand the significance of a transporter. In recent years my group has therefore developed and continues to improve a comprehensive and unbiased substrate search strategy for "orphan" transporters which is based on powerful analysis of cell lysates by HPLC linked to mass spectrometry. Application of this strategy, termed LC-MS Difference Shading, has led to:

 

  1. Discovery of the ergothioneine transporter ETT (gene symbol SLC22A4). Ergothioneine (ET) is a unique natural antioxidant which humans and other vertebrates can not synthesize themselves; it must be absorbed from food in which it is distributed very unevenly. The existence of a specific transporter suggests a beneficial role for ET. However, the precise physiological purpose of ET and the consequences of ET deficiency are still unclear. We work to understand the particular function of ET; since polymorphisms in the SLC22A4 gene are associated with susceptibility to chronic inflammatory diseases, this research may eventually help to design new therapies.
  2. Identification of a hepatic glutamate efflux transporter (OAT2, SLC22A7). We have also uncovered that OAT2 from human and rat efficiently transport orotic acid. Previous reports of hepatic release of glutamate into blood can now be explained by OAT2 activity. A specific OAT2 inhibitor could, by lowering plasma glutamate and thus promoting brain-to-blood efflux of glutamate, alleviate glutamate exotoxicity in acute brain conditions.