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Identification of competitive inhibitors of the human taurine transporter TauT in a human kidney cell line

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Richter,  Michelle
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Moroniak,  Selina J.
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Michel,  Hartmut
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Citation

Richter, M., Moroniak, S. J., & Michel, H. (2019). Identification of competitive inhibitors of the human taurine transporter TauT in a human kidney cell line. Pharmacological Reports, 71(1), 121-127. doi:10.1016/j.pharep.2018.10.005.


Cite as: http://hdl.handle.net/21.11116/0000-0002-BC6E-0
Abstract
Background: The osmolyte and antioxidant taurine plays an important role in regulation of cellular volume, oxidative status and Ca2+-homeostasis. Taurine uptake in human cells is regulated by the Na+- and Cl-dependent taurine transporter TauT. In order to gain deeper structural insights about the substrate binding pocket of TauT, a HEK293 cell line producing a GFP-TauT fusion protein was generated. Methods: Transport activity was validated using cell-based [3H]-taurine transport assays. We determined the Ka´m and IC50 values of taurine, β-alanine and γ-aminobutyrate. Additionally we were able to identify structurally similar compounds as potential new substrates or inhibitors of the TauT transporter. Substrate induced cytotoxicity was analyzed using a cell viability assay. Results: In this study we show competitive effects of the 3-pyridinesulfonate, 2-aminoethylhydrogen sulfate, 5-aminovalerate, β-aminobutyrate, piperidine-4-sulfonate, 2-aminoethylphosphate and homotaurine. We demonstrate that taurine uptake can be inhibited by a phosphate. Furthermore our studies revealed that piperidine-4-sulfonate interacts with TauT with a higher affinity than γ-aminobutyrate and imidazole-4-acetate. Conclusion: We propose that piperidine-4-sulfonate may serve as a potential lead structure for the design of novel drug candidates required for specific modulation of the TauT transporter in therapy of neurodegenerative diseases.