TSH, a glycoprotein hormone, is composed of alpha and beta subunits that determine receptor specificity. TSH is secreted from the pituitary gland in response to TRH stimulation from the hypothalamus. TRH binds to its receptor, activating a phospholipase C signaling cascade involving IP3, DAG, and calcium, which ultimately leads to increased TSH transcription, translation, and secretion. In the thyroid gland, TSH binding activates adenylate cyclase and increases cAMP, stimulating gene expression and thyroid hormone production and release. TSH levels are regulated by negative feedback from thyroid hormone levels and stimulation by TRH. Chronic TSH receptor stimulation can cause hyperthyroidism as seen in Graves' disease.

1. Thyroid Stimulating Hormone (TSH)
TSH (also called thyrotropin) is a member of the glycoprotein hormone family consists of two
subunits, the alpha and the beta subunit.
 The α (alpha) subunit has a 92-amino acid sequence. The α subunit is thought to be the
effector region responsible for stimulation of adenylate cyclase (involved the generation
of cAMP
 The β (beta) subunit (TSHB) is unique to TSH, and therefore determines its receptor
specificity.The β chain has a 118-amino acid sequence.
Synthesis and Secretion of TSH
Secretion 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 anterior
pituitary via the pituitary portal circulation and binds to a specific receptor located on TSH
secreting cells. There are two TRH receptors, identified as TRH-R1 and TRH-R2, both of which
are G-protein coupled receptors (GPCRs). only TRH-R1 is expressed at functional levels in the
anterior 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 as
increased 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 subunits
dissociate and activate Phospholipase C enzymes in the cell membrane. Activated PLC
hydrolysis PIP2 (phospholipid phosphatidylinositol 4,5-bisphosphate) yielding diacyl
glycerol (DAG) and inositol 1,4,5-triphosphate (IP3). DAG remains bound to the membrane, and
IP3 is released as a soluble structure into the cytosol. IP3 then diffuses through the cytosol to
bind to IP3 receptors, particular calcium channels in the endoplasmic reticulum (ER). These
channels are specific to calcium and allow the passage of only calcium to move through. This
causes the cytosolic concentration of Calcium to increase, causing a cascade of intracellular
changes and activity.In addition, calcium and DAG together works to activate PKC,which goes
on to phosphorylate other molecules, leading to altered cellular activity including gene targeting
proteins and cellular proteins. Gene targeting proteins mediate transcription factors for the
synthesis of alpha and beta subunits of TSH while cellular proteins mediate post translational
glycosylation of TSH and some contractile proteins activation which are involved in release of
TSH 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, 2014
The established biological function of the TSH receptor (TSHR) in the thyroid gland is to
regulate synthesis and secretion of thyroid hormones from follicular thyroid cells; it also plays an
important role in controlling the growth and development of the thyroid gland. The TSHR is a G
protein-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 PLCβ.
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 resultant
increase in the intracellular concentration of cAMP leading to the activation of gene target
proteins and peroxidase enzyme through phosphorylation by Kinase A. gene target proteins
target genes responsible for the synthesis of thyroid hormones ( T3 and T4) in colloidal cavity
of follicles while peroxidase enzyme facilitate release of T3 and T4 from the follicular cells
along with uptake of iodine from blood into follicular cells of thyroid gland. TSH-binding to
its receptor also results in increased TSH synthesis and thyroid cell growth.
Regulation of TSH
The synthesis and release of TSH is controlled by two pathways. The first is exerted by
the level of T3 within thyrotropic cells which regulates TSH expression, translation and release
through negative feed back mechanism. The second regulation is of course exerted by TRH as
described above.
Related Abnormality:
Chronic stimulation of the TSHR leads to over activation of the cAMP pathway that in
turn 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.