Thyrotropin- Releasing Hormone TRH is a tripeptide with the structure pyroglutamyl- histidyl- proline amide (pGlu- His- Pro- NH2) in which the C- terminal carboxyl group is blocked by amidation and the N- terminal α- amino group is blocked by cyclization. Beside stimulating TSH secretion, TRH also stimulates prolactin secretion. TRH is not only produced in the hypothalamus but is widely distributed through the central nervous system where it functions as a neurotransmitter. TRH is also detected in the posterior pituitary and in different other tissues, but little is known about its role there.

Hypophysiotropic TRH is produced in neurons, the cell bodies of which are located in the paraventricular nucleus of the hypo thalamus. The biosynthesis of TRH involves the production of a large precursor protein (proTRH) which, in humans, con sists of a sequence of 242 amino acids. This proTRH contains six copies of the TRH progenitor sequence Gln- His- Pro- Gly, flanked at both sides by pairs of the basic amino acids Arg and/ or Lys (Figure 1). Cleavage of proTRH at the basic amino acids by prohormone convertases (e.g. PC1 and PC2) and further removal of remaining basic residues by carboxypeptidases results in the liberation of the progenitor sequences. A specific glutaminyl cyclase catalyses the formation of the pGlu ring at the N- terminus and a so- called peptidylglycine α- amidating mono- oxygenase con verts Pro- Gly to ProNH2 at the C- terminus. The processing of proTRH takes place in vesicles that transport mature TRH and intervening peptides along the axons of the TRH neurons to the median eminence, where they are released into the portal vessels of the hypophyseal stalk.

Fig1. Biosynthesis of TRH. The figure shows the several steps by which the TRH progenitor sequences in proTRH are processed to mature TRH.

TRH is transported over a short distance through the hypo physeal stalk to the anterior lobe of the pituitary, where it stimulates the production and secretion of TSH (and prolactin). These actions of TRH are initiated by its binding to the type 1 TRH receptor (TRHR1), which is expressed on both the thyrotrope (TSH- producing cell) and the lactotroph (prolactin- producing cell). T his receptor belongs to the family of G- protein- coupled receptors, characteristically containing seven transmembrane domains. Human TRHR1 is a protein consisting of 398 amino acids, and binding of TRH induces a change in its interaction with the trimeric G- protein, resulting in the stimulation of phospholipase C activity. The activated phospholipase C catalyses the hydrolysis of phosphatidylinositol- 4,5- diphosphate to the second messengers inositol- 1,4,5- triphosphate and diacylglycerol, which initiate a cascade of reactions, including an increase in cellular Ca2+ levels and protein kinase C activity, that ultimately stimulates the release as well as the synthesis of TSH (and prolactin) [3]. TRH stimulation of TSHβ gene expression is also dependent on the pituitary- specific transcription factor 1.

TRH is subject to rapid degradation in the blood as well as in different tissues. Although multiple enzymes are involved, a very important role is played by the TRH- degrading ectoenzyme TRHDE, which catalyses the cleavage of the pGlu- His bond:

This enzyme has been characterized as a zinc- containing metalloproteinase, which in humans consists of 1024 amino acids. It has a single transmembrane domain and is inserted in the plasma membrane such that most of the protein is exposed on the cell surface (ectopeptidase), in particular in brain, pituitary, liver, and lung. Enzymatic cleavage of the protein close to the cell mem brane releases most of the protein in a soluble and enzymatically active form into the circulation, representing the origin of plasma TRHDE. Plasma TRHDE appears to be derived mostly from the liver. In the brain and the pituitary, where the enzyme is probably located in close vicinity of the TRH receptor, TRHDE supposedly plays an important role in the local regulation of TRH bioavailability. TRHDE activity in the pituitary and in plasma is increased in hyperthyroidism and decreased in hypothyroidism, which may contribute to the negative feedback control of TSH secretion by thy roid hormone.

Thyroid- Stimulating Hormone

 TSH is a glycoprotein produced by the thyrotropic cells of the anterior pituitary. Like the other hypophyseal hormones luteinizing hormone and follicle- stimulating hormone, it is composed of two subunits. The α- subunit is identical and the β- subunit is homologous among the three hormones. Although hormone specificity is conveyed by the β- subunit, dimerization with the α- subunit is re quired for biological activity. Human TSH consists of 205 amino acids; 92 in the α- subunit and 113 in the β- subunit. It has a molecular weight of 28 kDa, 20% of which is contributed by three complex carbohydrate groups: two on the α- subunit and one on the β- subunit. The structure of these carbohydrate groups is important for the biological activity of TSH and is dependent on the stimulation of the thyrotrope by TRH. Changes in TSH glycosylation underlie the altered TSH bioactivity under certain circumstances, such as pituitary stalk compression.

In addition to the stimulation by TRH and negative feedback by thyroid hormone, TSH production and secretion is also subject to negative regulation by hypothalamic somatostatin and dopamine and by steroids such as cortisol.

TSH binds to a specific TSH receptor located in the plasma mem brane of the follicular cell. The human TSH receptor is a G- protein- coupled receptor which, is a protein consisting of 764 amino acids with an exceptionally long extracellular N- terminal domain. The TSH receptor is preferentially coupled to a Gs α- subunit of the trimeric G- protein. Binding of TSH to its receptor induces the dis sociation of the G- protein subunits, resulting in the activation of the membrane- bound adenylate cyclase and, thus, in the stimulation of cAMP formation as second messenger. The increased cAMP levels induce a series of events, including the activation of protein kinase A activity, that ultimately results in the stimulation of the biosynthesis and secretion of thyroid hormone. In particular, the expression of genes coding for key proteins for hormone production (e.g. the iodide transporter, thyroglobulin, and thyroid peroxidase) is increased through mechanisms that also in volve different thyroid- specific transcription factors such as TTF1, TTF2, and PAX8.

As discussed elsewhere in this section, hyperthyroidism is often caused by an autoimmune process in which TSH receptor- stimulating antibodies play an important role. Hyperthyroidism may also be caused by a hyperfunctioning adenoma. In most patients with a toxic adenoma, somatic mutations have been identified in the TSH receptor, which result in the constitutive activation of this receptor. In other patients, somatic mutations have been found in the Gs α- subunit that result in the constitutive activation of the G- protein in the absence of TSH. Together, mutations in the TSH receptor and the Gs α- subunit account for the majority of toxic adenomas. Also, germline, gain- of- function mutations have been identified in patients with congenital, non- autoimmune hyperthyroidism. Conversely, germline, loss- of- function mutations have been described in patients with TSH resistance. However, patients with TSH resistance may be clinically euthyroid because the partial defect in TSH receptor function is compensated by increased plasma TSH concentrations.

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مواضيع ذات صلة

Regulation of Thyroid Hormone Secretion : The Hypothalamic-Pituitary Thyroid Axis

Transport and Metabolism of Thyroid Hormones

−Secretion of T4 and T3 and Recycling of I

Thyroglobulin Storage, Endocytosis, and Breakdown

Thyroid Peroxidase and DUOX: Tyrosine Iodination and Coupling

Thyroglobulin

The Thyroid Epithelial Cell

Introduction to Thyroid Hormones

 Regulation of Calcemia and Calcium- Phosphorus Homeostasis

Biological Actions of Parathormone (PTH)

Synthesis, Secretion, Metabolism, and Mechanism of Action of Parathormone (PTH)

Regulation of Thyroid Hormone Secretion and TSH