35 - Thyroid Hormone Receptors Flashcards
Thyroid
o thyroid hormone is produced by the thyroid gland which is found in the neck bordering the trachea
o it is a butterfly shaped gland which secretes the thyroid hormone onto the bloodstream
What is the secretion of thyroid hormone controlled by?
The secretion of thyroid hormone is under the control of the hypothalamus and pituitary axis
What happens when the hypothalamus is stimulated?
When the hypothalamus is stimulated, it release thyrotropin releasing hormone (TRH) which acts on the pituitary cells to secrete thyroid stimulating hormone (TSH)
Where does TSH travel through?
This travels through the bloodstream to the thyroid gland and interacts with G protein coupled receptors, the thyroid hormone stimulating receptor, and this causes elevations in cAMP inside the throid
What does elevations in cAMP cause?
Elevations in cAMP release the thyroid hormones T3 and T4 (triiodothyronine and tetraiodothyronine) and these have a negative feedback effect on the hypothalamus and on the pituitary to maintain regular levels in T3 and T4 in the cell
What is T3?
The T3 is the active form of the hormone and in target cells t4 can be converted into T3
What does the stimuli determine?
The stimuli that are detected by the hypothalamus determine whether metabolism in the body should be increased
What is an example of the stimulus?
One example of a stimulus could be exposure, which would cause an increase in thyroid hormone secretion, which could upregulate genes associated with metabolism in order to generate heat to counteract the cold
The thyroid is made up of what?
The thyroid itself is made up of follicles
o Consisting of single cell structure, inside of which is called the colloid, which is a proteinaceous solution
o Inside the colloid there is a protein called thyroid globulin, which is tyrosine rich and serves as a source of T3 and T4 which are synthesised from the tyrosine’s of thyroid globulin
What makes T3 and T4?
o a mono-iodinated tyrosine plus a deiodinated tyrosine makes T3, and 2 deiodinated tyrosines make T4
o We can also synthesise a reverse T3, but it is an inactive form of the hormone
What are thyroid hormone receptors involved in?
Act on all cells in the body and are involved in:
o Increasing the basal metabolic rate
o Increased heat production (oxidative metabolism)
o Increase glucose and amino acid uptake into cells
o Mitochondria- increase number and size
o mRNA and mRNA polymerase activity
o protein synthesis
All achieved through regulation of nuclear receptor activity
What does TSH interact with?
TSH interacts with the TSH receptor on the thyroid gland
What do T3 and T4 do?
o Secretion of T3 and T4 which are transported into target cells by transporter enzymes
o However, T3 and T4 can pass through the cell membrane to a degree by diffusion
o T3 when they enter cells can interact, pass through the nuclear pore complex, interact with the nuclear receptor, the thyroid hormone receptor, which is a heterodimer with a retinoic acid receptor, and there is then exchange of co-regulators to co-activators
- Leads to new transcription and production of proteins
o T4 itself is converted into T3 in target cells through the action deiodinases, so there is the removal of an outer ring iodine to make T3
What can T3 be converted into?
T2
Characteristics of thyroid hormone transporters
- transported molecules (T4 and rT3)
- tissue location (brain - capillaries)
- possible physiological role ( transport of thyroid hormones across the blood-brain barrier)
- clinical phenotype in its absence (unknown)
Effects of single gene inactivations related to the thyroid hormone pathway in knockout mouse models and humans
- peripheral tissue euthyroidism
- partial perinatal mortality
- growth retardation
- impaired fertility
HYPOthyroid diseases
- cretinism
- myxoedema
- goiter
Cretinism
Hypothyroidism in infancy and childhood leads to stunted growth and intelligence
o Can be corrected by giving thyroxine if started early enough
Myxoedema
Hypothyroidism in adults leads to lowered metabolic rate and vigour
o Corrected by giving thyroxine
Goiter
Enlargement of the thyroid gland. Can be caused by:
o Inadequate iodine in the diet with resulting low levels of T4 and T3
o An autoimmune attack against components of the thyroid gland (called Hashimoto’s thyroiditis)
HYPERthyroid diseases
- Graves’ disease
- osteoporosis
Graves’ disease
Autoantibodies against the TSH receptor bind to the receptor mimicking the effect of TSH binding
o Result:
- Excessive production of thyroid hormones
o Graves’ disease is an example of an autoimmune disease
Osteoporosis
High levels of thyroid hormones suppress the production of TSH through a negative feedback mechanism
o The resulting low level of TSH causes an increase in the numbers of bone-reabsorbing osteoclasts resulting in osteoporosis
Thyroid hormone receptors
o Thyroid hormones promote the synthesis of adrenoceptors
o Therefore, in hyperthyroidism some of the symptoms look like over-activity of the sympathetic nervous system
o Can be treated with beta-adrenoceptor antagonists
