Triiodothyronine

Triiodothyronine, C₁₅H₁₂I₃NO₄, also known as T₃, is a thyroid hormone.

Thyroid-stimulating hormone (TSH) activates the production of thyroxine (T₄) and T₃. This process is under regulation. In the hypothalamus, T₄ is converted to T₃. TSH is inhibited mainly by T₃. The thyroid gland releases greater amounts of T₄ than T₃, so plasma concentrations of T₄ are 40-fold higher than those of T₃. Most of the circulating T₃ is formed peripherally by deiodination of T₄ (85%), a process that involves the removal of iodine from carbon 5 on the outer ring of T₄. Thus, T₄ acts as prohormone for T₃.

This thyroid hormone is similar to thyroxine but with one fewer iodine atoms per molecule. In addition, T₃ exhibits greater activity and is produced in smaller quantity.

It is the most powerful thyroid hormone, and affects almost every process in the body, including body temperature, growth, and heart rate.

Production of T₃

T₃ is metabolically active hormone that is produced from T₄. T₄ is deiodinated by two deiodinases to produce the active triiodothyronine:
1. Type I present within the liver and accounts for 80% of the deiodination of T₄
2. Type II present within the pituitary.

T₄ is synthesised in the thyroid gland follicular cells as follows.
1. The Na⁺/I^- symporter transports two sodium ions across the basement membrane of the follicular cells along with an iodine ion. This is secondary active transporter that utilises the concentration gradient of Na⁺ to move I^- against its concentration gradient.
2. I^- is moved across the apical membranae into the colloid of the follicle.
3. Thyroperoxidase oxidises two I^- to form I₂. Iodide is non-reactive and only the more reactive iodine is required for the next step.
4. The thyroperoxidase iodinates the tyrosyl residues of the thyroglobulin within the colloid. The thyroglobulin was synthesis in the ER of the follicular cell and secreted into the colloid.
5. Thyroid stimulating hormone (TSH) released from the pituitary gland binds the TSH receptor (a G_s protein coupled receptor) on the basolateral membrane of the cell and stimulates the endocytosis of the colloid.
6. The endosytosed vesicles fuse with the lysosomes of the follicular cell. The lysosomal enzymes cleave the T₄ from the iodinated thyroglobulin.
7. These vesicles are then exocytosed releasing the thyroid hormones.

In the follicular lumen, tyrosine residues become iodinated. This reaction requires hydrogen peroxide. Iodine bonds carbon 3 or carbon 5 of tyrosine residues of thyroglobulin in a process called organification of iodine. The iodination of specific tyrosines yields monoiodotyrosine (MIT) and diiodotyrosine (DIT). One MIT and one DIT are enzymatically coupled to form T₃. The enzyme is thyroid peroxidase.

Transport of Triiodothyronine

The T₃ (and T₄) bind to nuclear receptors, thyroid receptors. However, T₃ (and T₄) are not very lipophilic and as a result, are unable to pass through the phospholipid bilayers. They therefore have specific transport proteins on the cell membranes of the effector organs which allow the T₃ and T₄ to pass into the cells. The thyroid receptors bind to response elements in gene promoters and thus enabling them to activate or inhibit transcription. The sensitivity of a tissue to T₃ is modulated through the thyroid receptors.

Mechanism of Action

T₃ and T₄ are carried in the blood bound to plasma proteins. This has the effect of increasing the half life of the hormone and decreasing the rate at which it is taken up by peripheral tissues. There are three main proteins that the two hormones are bound to. Thyronine binding globulin (TBG) is a gylcoprotein that has a higher affinity for T₄ than for T₃. The second plasma protein to which the hormone bind is transthyretin (which has a higher affinity for T₃ than for T₄. Both hormones bind with a low affinity to albumin, but due to the large availability of albumin it has a high capacity.

Effects of T₃

T₃ increases the basal metabolic rate and thus increases the body's oxygen and energy consumption. The basal metabolic rate is the minimal caloric requirement needed to sustain life in a resting individual. T₃ acts on the majority of tissues within the body, with a few exceptions including the brain, spleen and testis. It increases the production of the Na⁺/K⁺ -ATPase and in general increases the turnover of different endogenous macromolecules by increasing their synthesis and degradation.

Protein
T₃ stimulates the production of RNA Polymerase I and II and therefore increases the rate of protein synthesis. It also increases the rate of protein degradation and in excess the rate of protein degradation exceeds the rate of protein synthesis. In such situations the body may go into negative ion balance.

Glucose
T₃ potentiates the effects of the β-adrenergic receptors on the metabolism of glucose. It therefore increases the rate of glycogen breakdown and glucose synthesis in gluconeogenesis. It also potentiates the effects of insulin, which have opposing effects.

Lipids
T₃ stimulates the breakdown of cholesterol and increases the number of LDL receptors, therefore increasing the rate of lipolysis.

T₃ also affects the cardiovascular system. It increases the cardiac output by increasing the heart rate and force of contraction. This results in increased systolic blood pressure and decreased diastolic blood pressure. The latter two effects act to produce the typical bounding pulse seen in hyperthyroidism.

T₃ also has profound effect upon the developing embryo and infants. It affects the lungs and influences the postnatal growth of the central nervous system. It stimulates the production of myelin, neurotransmitters and axon growth. It is also important in the linear growth of bones.

The effects of abnormal thyroid functions

Goitre
Goitre is the swelling of the thyroid gland.
It is often associated with iodine deficiency. The lack of iodine decreases the production of the thyroid hormones T₃ and T₄. These hormones usually act on the pituitary gland to decrease the release of thyroid stimulating hormone (TSH) by negative feedback. Lack of this feedback causes the systemic levels of TSH to increase. One of the actions of TSH (aside from stimulating the release of the thyroid hormones) is to stimulate the growth of the thyroid gland. However, usually the enlarged thyroid will then act normally to trap sufficient iodine and thus the levels of T₃ and T₄ are normal.
Goitre may also be a result of Grave's disease or of a tumour.

Hyperthyroidism
High levels of T₃
. The symptoms of hyperthyroidism include:

• Raised basal metabolic rate
• Bounding pulse
• Heat intolerance
• Weight loss (often accompanied by increased appetite)
• Increased sympathetic drive
• Eye protrusion

Hyperthryoidism may be caused by Grave's disease, an autoimmune disease where immunoglobulins that resemble TSH cause constitutive release of high levels of the thyroid hormones. On the other hand it may be due to a tumour of the thyroid gland.

Hypothyroidism
Low levels of T₃
If this occurs during childhood it can result in gross deficiencies of myelination of the central nervous system neurons and stunting of growth due to decreased growth of the long bones. Hypothyroidism in the adult is known as myxedema, a condition where a reduced metabolism, slow mentation, hypothermia and constipation are seen (due the lack of gut motility stimulated by T₃). A cause of hypothyroidism is thyroid hormone deficiency, a genetic defect that reduces the hormone binding.