TSHR - Thyroid Stimulating Hormone Receptor | Elisa - Clia - Antibody - Protein

Background

• TSHR is a G protein-coupled receptor primarily expressed in the thyroid gland, where it plays a central role in regulating thyroid hormone synthesis and secretion. TSHR mediates the biological effects of thyroid-stimulating hormone (TSH), also known as thyrotropin, which is secreted by the anterior pituitary gland. TSH, a glycoprotein hormone composed of alpha and beta subunits, binds to and activates TSHR. Activation of Gs leads to the stimulation of adenylate cyclase, resulting in an increase in cAMP levels. Elevated cAMP activates protein kinase A (PKA), which in turn regulates various downstream effects, including thyroid hormone synthesis and secretion, and thyroid cell growth and differentiation. TSHR activity is tightly regulated by factors such as thyroid hormone levels (negative feedback), thyroid-releasing hormone (TRH) from the hypothalamus, and autoantibodies targeting TSHR in autoimmune thyroid diseases. Dysregulation of TSHR signaling can lead to thyroid disorders with significant clinical implications, highlighting its importance as a therapeutic target in the management of thyroid diseases.

Structure:

Extracellular Domain (ECD):

1. The ECD is responsible for binding the thyroid-stimulating hormone (TSH). It is a large domain composed of several subdomains that contribute to the high-affinity and specificity of the hormone binding.
2. Leucine-Rich Repeat (LRR) Domain: This domain within the ECD contains several leucine-rich repeats that form a horseshoe-like structure. These repeats are critical for TSH binding.
3. Cysteine-Rich Region: Following the LRR domain, this region plays a role in the structural integrity and proper folding of the receptor.
4. Hinge Region: This region connects the extracellular hormone-binding domain to the transmembrane domain. It contains a cleavage site for proteolytic processing, which is important for receptor maturation and function.

Transmembrane Domain (TMD):

1. The TMD consists of seven alpha-helices that span the cell membrane. This helical structure is characteristic of all GPCRs.
2. Helices: The seven transmembrane helices are arranged in a way that allows the receptor to undergo conformational changes upon hormone binding, leading to the activation of intracellular signaling pathways.

Intracellular Domain:

1. The intracellular domain interacts with G proteins and other intracellular signaling molecules. This domain is crucial for transmitting the signal from the extracellular hormone binding to the intracellular signaling machinery.
2. G Protein Binding Sites: Specific regions within the intracellular loops and the C-terminal tail are responsible for binding to G proteins, primarily the Gs protein, which activates adenylate cyclase and increases cyclic AMP (cAMP) levels.

Physiological Functions:

• Thyroid Hormone Synthesis: TSHR activation in thyroid follicular cells stimulates iodine uptake, thyroid hormone synthesis (thyroxine - T4 and triiodothyronine - T3), and secretion into the bloodstream.
• Thyroid Gland Growth: TSHR activation also promotes thyroid gland growth and enlargement (thyroid hypertrophy), known as goiter, in response to increased TSH stimulation.

Clinical Implications:

• Mutations or dysregulation of TSHR can lead to thyroid disorders such as hyperthyroidism (overactive thyroid) or hypothyroidism (underactive thyroid).
• Autoimmune thyroid diseases, such as Graves' disease and Hashimoto's thyroiditis, are associated with the presence of stimulating or blocking autoantibodies targeting TSHR.

Therapeutic Potential:

• Drugs targeting TSHR, such as thyroid hormone replacement therapy (levothyroxine) for hypothyroidism and antithyroid drugs (e.g., thionamides) for hyperthyroidism, are used clinically for the management of thyroid disorders.
• Radioactive iodine (RAI) therapy, which targets and destroys thyroid tissue, is also used to treat hyperthyroidism and thyroid cancer by exploiting the overexpression of TSHR in thyroid follicular cells.