The thyrotropin receptor in Graves' disease.

The application of molecular biology to the study of the thyrotropin receptor (TSHR) has led to major advances in our understanding of its structure, function, and relationship to the pathogenesis of Graves' disease. This review summarizes many of these features and also provides a personal perspective, questioning some assumptions and general concepts, as well as describing remaining challenges. Among the issues raised are the limits in our understanding of the spatial orientation of the structural domains of the TSHR, including the enigmatic hinge region. We review the phenomenon of TSHR intramolecular cleavage, the shedding of the A-subunit component of the ectodomain, and the importance of the latter in generating thyroid-stimulating antibodies. The epitopes of thyroid-stimulating and -blocking autoantibodies have been a confusing and controversial subject that requires review and evaluation of available data. Finally, we address the potential physiological or pathophysiological significance of TSHR multimerization in TSHR. Taken together, this review will, hopefully, convey the fascination and excitement that molecular biology has contributed to the study of the TSHR, especially as it relates to the pathogenesis of Graves' disease.