## Mechanism of TSH Action on Thyroid **Key Point:** TSH (thyroid-stimulating hormone) is a glycoprotein hormone secreted by anterior pituitary thyrotroph cells that regulates both thyroid hormone synthesis and secretion. ### Signal Transduction Pathway 1. **Receptor Binding**: TSH binds to TSH receptors (TSH-R), which are G-protein coupled receptors (GPCRs) on the basolateral membrane of thyroid follicular cells. 2. **G-Protein Activation**: Binding activates Gs proteins, which stimulate adenylyl cyclase. 3. **cAMP Generation**: Increased intracellular cAMP concentration activates protein kinase A (PKA). 4. **Downstream Effects**: PKA phosphorylates multiple target proteins, leading to: - Increased iodine uptake via sodium-iodide symporter (NIS) - Increased thyroid peroxidase (TPO) activity - Enhanced thyroglobulin synthesis - Increased endocytosis of colloid - Proteolysis of thyroglobulin and release of T~3~ and T~4~ **High-Yield:** The cAMP-PKA pathway is the primary mechanism for acute TSH effects. Chronic TSH stimulation also increases thyroid cell proliferation and gland size (hyperplasia). **Clinical Pearl:** This mechanism explains why TSH receptor antibodies in Graves' disease mimic TSH action and cause unregulated thyroid hormone production independent of normal feedback control. ### Comparison with Other Hormone Mechanisms | Hormone | Receptor Type | Second Messenger | Target Effect | |---------|---------------|------------------|---------------| | TSH | GPCR (Gs) | cAMP → PKA | Thyroid hormone synthesis & secretion | | LH/FSH | GPCR (Gs) | cAMP → PKA | Gonadal steroid synthesis | | ACTH | GPCR (Gs) | cAMP → PKA | Cortisol synthesis | | Insulin | Tyrosine kinase | MAPK/PI3K | Glucose uptake & metabolism | **Mnemonic:** **G-CAMP** = G-protein coupled receptor → cAMP → Adenylyl cyclase → Mediates PKA activation → Phosphorylation cascade
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