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

• Published in: Journal of evolutionary biochemistry and physiology Vol. 58; no. 5; pp. 1439 - 1454
• Main Authors: Fokina, E. F., Shpakov, A. O.
• Format: Journal Article
• Language: English
• Published: Moscow Pleiades Publishing 01-09-2022; Springer Nature B.V
• Subjects: Allosteric properties; Animal Physiology; Antagonists; Autoantibodies; Biochemistry; Biomedical and Life Sciences; Evolutionary Biology; Hypothyroidism; Immunogenicity; Inverse agonists; Life Sciences; Regulation; Reviews; Thyroid cancer; Thyroid gland; Thyroid-stimulating hormone; Thyroid-stimulating hormone receptors; thyroid-stimulating hormone; allosteric regulator; autoimmune hyperthyroidism; thyrotropin receptor; thyroid; thyroid hormone; transmembrane domain
• ISSN: 0022-0930; 1608-3202
• DOI: 10.1134/S0022093022050143

One of the key elements responsible for the thyroid response to thyroid-stimulating hormone (TSH) is the TSH receptor (TSHR), which belongs to the G protein-coupled receptor superfamily. Binding of TSH or stimulatory autoantibodies to the TSHR extracellular domain triggers multiple signaling pathways in target cells that are mediated through various types of G proteins and β-arrestins. Inhibitory autoantibodies, in contrast, suppress TSHR activity, inducing hypothyroid states. Activating mutations lead to constitutively active TSHR forms and can trigger cancer. Therefore, the TSHR is one of the key targets for the regulation of thyroid function and thyroid status, as well as correction of diseases caused by changes in TSHR activity (autoimmune hyper- and hypothyroidism, Graves’ ophthalmopathy, thyroid cancer). TSH preparations are extremely rarely used in medicine due to their immunogenicity and severe side effects. Most promising is the development of low-molecular allosteric TSHR regulators with an activity of full and inverse agonists and neutral antagonists, which are able to penetrate into the allosteric site located in the TSHR transmembrane domain and specifically bind to it, thus controlling the ability of the receptor to interact with G proteins and β-arrestins. Allosteric regulators do not affect the binding of TSH and autoantibodies to the 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 of regulating TSHR activity, including the possibility of using ligands of its allosteric sites.