TSH hormone

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  • 1. Thyroid Stimulating Hormone (TSH)TSH (also called thyrotropin) is a member of the glycoprotein hormone family consists of twosubunits, the alpha and the beta subunit. The (alpha) subunit has a 92-amino acid sequence. The subunit is thought to be theeffector region responsible for stimulation of adenylate cyclase (involved the generationof cAMP The (beta) subunit (TSHB) is unique to TSH, and therefore determines its receptorspecificity.The chain has a 118-amino acid sequence.Synthesis and Secretion of TSHSecretion of TSH is stimulated by thyrotropin-releasing hormone (TRH) from the hypothalamus.TRH, a tripeptide, is synthesized by neurons in hypothalamus and is transported to the anteriorpituitary via the pituitary portal circulation and binds to a specific receptor located on TSHsecreting cells. There are two TRH receptors, identified as TRH-R1 and TRH-R2, both of whichare G-protein coupled receptors (GPCRs). only TRH-R1 is expressed at functional levels in theanterior pituitary. Binding of TRH to its receptor activates a typical Phospholipase C (PLC) -mediated signaling cascade. The TRH- induced signaling leads to TSH secretion as well asincreased TSH transcription and post-translational glycosylation.Phospholipase C (PLC) -mediated signaling cascade. (IP3/DAG Pathway):TRH receptors are G protein bounded receptors. When TRH binds to TRHR, G-Protein subunitsdissociate and activate Phospholipase C enzymes in the cell membrane. Activated PLChydrolysis PIP2 (phospholipid phosphatidylinositol 4,5-bisphosphate) yielding diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). DAG remains bound to the membrane, andIP3 is released as a soluble structure into the cytosol. IP3 then diffuses through the cytosol tobind to IP3 receptors, particular calcium channels in the endoplasmic reticulum (ER). Thesechannels are specific to calcium and allow the passage of only calcium to move through. Thiscauses the cytosolic concentration of Calcium to increase, causing a cascade of intracellularchanges and activity.In addition, calcium and DAG together works to activate PKC,which goeson to phosphorylate other molecules, leading to altered cellular activity including gene targetingproteins and cellular proteins. Gene targeting proteins mediate transcription factors for thesynthesis of alpha and beta subunits of TSH while cellular proteins mediate post translationalglycosylation of TSH and some contractile proteins activation which are involved in release ofTSH from TSH releasing cells of pituitary gland into blood stream.

2. PLC mediated cleavage of PIP2 to DAG and IP3 3. The TSH receptor and its role in the thyroid 2nd October, 2014The established biological function of the TSH receptor (TSHR) in the thyroid gland is toregulate synthesis and secretion of thyroid hormones from follicular thyroid cells; it also plays animportant role in controlling the growth and development of the thyroid gland. The TSHR is a Gprotein-coupled receptor with seven membrane spanning segments, three extracellular loops,three intracellular loops, an amino terminal ectodomain and an intracellular carboxy terminal.The receptors are coupled through G-protein activation of adenylate cyclase as well as PLC.TSH binding to its receptor triggers a signaling cascade that results in increased cAMP, PKA,IP3, and DAG.In the thyroid, TSH binding predominantly activates adenylate cyclase with a resultantincrease in the intracellular concentration of cAMP leading to the activation of gene targetproteins and peroxidase enzyme through phosphorylation by Kinase A. gene target proteinstarget genes responsible for the synthesis of thyroid hormones ( T3 and T4) in colloidal cavityof follicles while peroxidase enzyme facilitate release of T3 and T4 from the follicular cellsalong with uptake of iodine from blood into follicular cells of thyroid gland. TSH-binding toits receptor also results in increased TSH synthesis and thyroid cell growth.Regulation of TSHThe synthesis and release of TSH is controlled by two pathways. The first is exerted bythe level of T3 within thyrotropic cells which regulates TSH expression, translation and releasethrough negative feed back mechanism. The second regulation is of course exerted by TRH asdescribed above.Related Abnormality:Chronic stimulation of the TSHR leads to over activation of the cAMP pathway that inturn causes thyroid hyperplasia and hyperthyroidism. This process occurs in Graves' disease(GD), the commonest cause of hyperthyroidism in which thyroid stimulating antibodies (TSAB)bind the receptor and mimic the action of TSH.