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. 

PLC mediated cleavage of PIP2 to DAG and IP3

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.