Thyroid-Stimulating Hormone Receptor: the Role in the Development of Thyroid Pathology and Its Correction

Abstract

One of the key elements responsible for the thyroid responseto thyroid-stimulating hormone (TSH) is the TSH receptor (TSHR),which belongs to the G protein-coupled receptor superfamily. Bindingof TSH or stimulatory autoantibodies to the TSHR extracellular domaintriggers multiple signaling pathways in target cells that are mediatedthrough various types of G proteins and β-arrestins. Inhibitoryautoantibodies, in contrast, suppress TSHR activity, inducing hypothyroid states.Activating mutations lead to constitutively active TSHR forms andcan trigger cancer. Therefore, the TSHR is one of the key targetsfor the regulation of thyroid function and thyroid status, as wellas correction of diseases caused by changes in TSHR activity (autoimmunehyper- and hypothyroidism, Graves’ ophthalmopathy, thyroid cancer).TSH preparations are extremely rarely used in medicine due to theirimmunogenicity and severe side effects. Most promising is the developmentof low-molecular allosteric TSHR regulators with an activity offull and inverse agonists and neutral antagonists, which are ableto penetrate into the allosteric site located in the TSHR transmembranedomain and specifically bind to it, thus controlling the abilityof the receptor to interact with G proteins and β-arrestins. Allostericregulators do not affect the binding of TSH and autoantibodies tothe receptor, which enables mild and selective regulation of thyroid function,while avoiding critical changes in TSH and thyroid hormone levels.The present review addresses the current state of the problem ofregulating TSHR activity, including the possibility of using ligandsof its allosteric sites.