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The Human Thyrotropin Receptor Is Predominantly Internalized by ß-Arrestin 2

III Medical Department, University of Leipzig, 04103 Leipzig, Germany

Address all correspondence and requests for reprints to: R. Paschke, M.D., III Medical Department, University of Leipzig, Philipp-Rosenthal- Strasse 27, D-04103 Leipzig, Germany. E-mail: pasr{at}medizin.uni-leipzig.de.

The ß-arrestin-dependent endocytosis of the ß₂-adrenergic receptor (ß₂AR) has been demonstrated by confocal fluorescence microscopy. Furthermore, a constitutively activated ß₂AR is also constitutively desensitized and down-regulated. To clarify the function of ß-arrestin 1 or 2 for TSH receptor (TSHR) desensitization and examine whether constitutively activated TSHR mutants are internalized in a different way, we investigated the TSHR trafficking in association with ß-arrestins in cotransfection experiments in HEK 293 cells using confocal laser-scanning microscopy. We found that both ß-arrestins are able to internalize the TSHR in HEK 293 cells. However, whereas the ß-arrestin 1-mediated TSHR internalization reached its maximum 20 min after TSH stimulation, the ß-arrestin 2-mediated TSHR internalization already reached its maximum 5 min after TSH stimulation. Furthermore, an increased basal desensitization and internalization of constitutively activated TSHR mutants N670S, S505N, and F631L cotransfected with ß-arrestin 2 could not be found. After TSH stimulation the constitutively activated mutants showed the same time course for internalization as the wild-type-TSHR. In summary, contrary to data obtained for the ß₂AR, the constitutive activation of the TSHR does not influence the desensitization and time course for internalization of the receptor, and in agreement with findings for the FSH and LH receptors, these results characterize the TSH receptor as a member of the class A of G protein-coupled receptors, which have a higher affinity to ß-arrestin 2 than ß-arrestin 1 and do not colocalize with ß-arrestins in endosomes.

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