TSH Receptor

The thyrotropin receptor (or TSH receptor) is a receptor (and associated protein) that responds to thyroid-stimulating hormone (also known as "thyrotropin") and stimulates the production of thyroxine (T4) and triiodothyronine (T3). The TSH receptor is a member of the G protein-coupled receptor superfamily of integral membrane proteins and is coupled to the Gs protein.

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Background


An Overview of TSH Receptor

Thyroid stimulating hormone receptor (TSH receptor, or TSHR) is a transmembrane receptor that receives thyrotropin signaling and stimulates cells to produce thyroid hormones. TSHR is a specific protein of thyroid cells that is present on the thyroid follicular cell membrane. The primary function of TSHR is to bind to thyroid stimulating hormone (TSH), which activates the G protein-adenylate cyclase-cAMP and phospholipase C signaling systems, activates G-protein coupling, and undergoes intracellular cascades. This will promote the synthesis, secretion of thyroid hormones and the growth of thyroid cells.

Inhibition of TSHR

TSHR is a major molecule regulating thyroid cell function, and activation of TSHR is important for the treatment of thyroid-related diseases. Currently, rhTSH (recombinant human TSH) is a drug that clinically activates thyroid tumors and Graves' disease by activating TSHR function. rhTSH is a recombinant protein that is often difficult to detect relative to small molecules in terms of purity, quality control, and production of large amounts of protein. Therefore, TSHR small molecule agonists are significant. In 2009, the first TSHR agonist (NCGC00161870) was reported. NCGC00161870 has a relatively high affinity with TSHR and has a certain specificity. One of the ideal drugs for the treatment of Graves' disease is an antagonist of TSHR. Antagonists inhibit TSHR autoantibody-activated receptors without compromising TSH signaling. The current research focus is to use computer virtual screening and high-throughput screening methods to find signaling pathways that activate or block TSHR transmembrane helix regulation. This may reveal new and more promising TSHR small molecule activators or antagonists.

TSHR and diseases

TSHR plays an important role in regulating the development and progression of thyroid diseases such as Graves disease and thyroid cancer. As a member of the superfamily of G-protein coupled receptors (GPCRs), TSHR is the main antigen of autoimmune thyroid disease and is expected to be a therapeutic target for Graves' disease. As Graves' disease In addition, TSHR is also an important protein regulating the occurrence and development of thyroid cancer, and therefore a potential target for the diagnosis and treatment of thyroid cancer.

Reference:

Davies T.F., Latif R. (2015) Targeting the thyroid-stimulating hormone receptor with small molecule ligands and antibodies. Expert Opin Ther Targets, 19(6): 835-847.