Endocrine Abstracts

The Thyrotropin receptor (TSHR) is known as the important key-player for regulation of thyroid growth and function. As a G-protein coupled receptor (GPCR) TSHR predominantly activates the Gs/adenylyl cyclase and the Gq/11 phospholipase C signaling pathways, that finally regulate thyroid hormone production. Aberrant thyroid hormone production can be caused by activating TSHR mutations in case of toxic thyroid nodules or non-autoimmune hyperthyroidism or via inactivating mutations identified in patients suffering from hyperthyrotropinemia, TSH resistance or congenital hypothyroidism. Careful functional characterization of naturally occurring TSHR mutations and huge efforts from side-directed mutagenesis studies combined with fragmental structural information have widened our knowledge of signaling related processes at the TSHR significantly. In addition, it is recognized that the TSHR functions as a dimer or oligomer, which is of importance to understand specificities of patient phenotypes caused by heterozygous inactivating TSHR mutations. Strikingly, the available information is a prerequisite for understanding the role of TSHR under different physiological and pathophysiological conditions, which is also important for the development of artificial ligands that modulate controlled TSHR functions. However, several details of the TSHR are still unknown like the assembly of the entire receptor protein and the interplay between receptor components during signal transduction. For that reason, even after nearly twenty years of TSHR mutational screening, naturally occurring mutations are still helpful to reveal new insights into such missing information. Recently identified mutations for example prompted to details of the sixth transmenbrane helix during receptor activation and inactivation, or to a potential relationship between activating mutations and a TSHR oligomer constellation. Under these perspectives latest insights into pathogenic malfunctions are still of enormous importance also to complete the understanding of the TSHR regulation mechanisms and related physiological processes.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details are unavailable.