Molecular Mechanisms of Thyroid-Stimulating Hormone Receptor Regulation – From Signaling to Drug Development

The thyroid stimulating hormone (TSH) receptor, which specifically binds TSH and thyrostimulin, is a key component of the thyroid system that controls a wide range of vital processes in humans and vertebrates. This receptor is structurally similar to gonadotropin receptors. It also has a large ectodomain with an orthosteric site for hormone binding, a transmembrane domain that interacts with heterotrimeric G proteins and β-arrestins and in the internal cavity of which allosteric sites are localized, and is also capable of forming functionally active homodi(oligo)meric complexes. In pathology, antibodies with different profiles of biological activity are produced against the extracellular regions of the TSH receptor, causing autoimmune diseases of the thyroid gland. The efficiency of TSH interaction with the orthosteric site and the selectivity of stimulation of a certain intracellular cascade are controlled by a number of allosteric mechanisms and regulators, including the N-glycosylation status of TSH molecules, complex formation of the TSH receptor, localization of the “internal” agonist in its hinge loop, and the lipid composition of the membrane. This review is devoted to the mechanisms of orthosteric and allosteric regulation of TSH receptor activity, their relationships, as well as the role of changes in TSH receptor activity in the development of autoimmune diseases and thyroid cancer, Graves’ ophthalmopathy, and osteoporosis. It also considers achievements in the development of low-molecular allosteric regulators of the TSH receptor and the prospects for their possible use in medicine.