5 - Thyroid Hormones Flashcards
What is the functional unit of the thyroid gland?
Follicles
- Follicular cells are arranged around a central cavity (lumen)
- This lumen contains colloid, which is a protein-rich fluid
What are parafollicular cells?
The cells that surround the follicles
- These cells produce calcitonin
What is the main source of iodine?
The diet
How is iodine accumulated by the thyroid follicular cells?
***Objective
- Iodide is concentrated by follicular cells in an energy-dependent manner.
- The energy of the sodium electrochemical gradient across the cell membrane powers uptake of iodide.
- The iodide ions exit the follicular cell and enter the lumen of the follicle via an iodide channel located in the apical membrane.
- This is a passive process, with iodide ions flowing down their concentration gradient.
What is thyroglobulin?
- Thyroid hormones are derived from thyroglobulin, a large, homodimeric glycoprotein
- Thyroglobulin is made by the follicular cells and secreted through the apical membrane into the lumen of the follicles, where it forms the major component of colloid
What is meant by organification of iodine?
Incorporation of iodine into thyroglobulin is referred to as the organification of iodine
Why is iodine needed?
Iodinated thyroglobulin molecules are coupled together to form T3 and T4 - thyroid hormones
What enzyme is responsible for the organification of iodine?
Thyroid peroxidase
Thyroid peroxidase is a
What does this enzyme (thyroid peroxidase) require for activity?
*** Objective
- Iodide ions (a reducing agent aka electron donor)
- Hydrogen peroxide
Iodide ions reduce hydrogen peroxide to water
The hydrogen peroxide comes from calcium-dependent NADPH oxidases, which are located near thyroid peroxidase
What happens to the oxidized iodine?
I- is oxidized to I (atomic iodine)
- Iodine reacts with tyrosine residues found within a thyroglobulin molecule
What forms from iodine and tyrosine found within thyroglobulin?
Monoiodothyronine (MIT)
What does MIT react with?
MIT can react with another iodine to form diiodothyronine (DIT)
In terms of thyroid hormone synthesis, what is meant by ‘coupling’?
*** Objective
Thyroid peroxidase enzyme functions to couple MIT with DIT or couple DIT with another DIT
These form T3 (MIT/DIT) or T4 (DIT/DIT)
Does the thyroid gland have the capacity to store hormone?
*** Objective
Yes
How does the thyroid gland store hormone?
*** Objective
There is a lot of iodinated thyroglobulin in colloid, meaning that the thyroid can just keep it there and store it
There is a 2 – 3 months supply of thyroid hormone in a normal, healthy individual
What does the release of T3 and T4 require?
*** Objective
Proteolysis of thyroglobulin
Describe the process of T3 and T4 release
*** Objective
- Thyroglobulin (big molecule which tyrosin is on) is taken back up into the follicular cells by an endocytic process
- The endocytic vesicles take the thyroglobulin to the lysosome
- A process of proteolysis releases T3, T4, MIT, DIT, peptides and free amino acids
- T3 and T4 are then trafficked out of the cell
- MIT and DIT are de-ioninated in order to conserve iodine for re-use
Which is more abundant, T3 or T4?
*** Objective
T4
More T4 is formed than T3
Typical ratio is 5-7 T4 for every T3
Which is the more biologically active hormone, T3 or T4?
*** Objective
T3
Both T3 and T4 are biologically active in their “free” form, but more T3 is free than T4, so it is considered to be more biologically active
Where does the conversion of T4 to T3 occur?
*** Objective
About 40% of T4 is converted to T3, particularly in the liver and kidneys
How does the conversion of T4 to T3 occur?
*** Objective
Deiodination
There are three classes of deiodinated enzymes (deiodinases)
What process accounts for thyroglobulin found in the serum?
*** Objective
Transcytosis
Certain endocytic vesicles are routed from the apical membrane to the basolateral membrane, where they thyroglobulin that they contain is released into the bloodstream by exocytosis
What is the clinical significance of thyroglobulin in the serum via transcytosis?
*** Objective
Can be a sign of…
- Thyroiditis
- Graves disease
- Thyroid malignancy
Describe how thyrotropin releasing hormone (TRH) signals thyroid stimulating hormone (TSH; thyrotropin) release.
*** Objective
- Parvicellular neurons of the hypothalamus release TRH
- TRH goes to the anterior pituitary via the portal hypophysial system
- TRH binds to a G-protein receptor
- Phospholipase C is activated
- Calcium is released, which triggers exocytosis of vesicles containing TSH (thyroid stimulating hormone; thyrotropin)
What are the roles of TSH?
*** Objective
- Triggers a signaling cascade
- Stimulates all aspects of thyroid hormone synthesis/secretion
- Stimulates growth of thyroid gland
- Has multiple effects on thyroid-specific transcription factors
How is the TSH signal transduced?
*** Objective
Via binding to the TSH G-protein coupled receptor
- This stimulates a signaling cascade
- This involves both adenylate cyclase and phospholipase C
How are thyroid hormones regulated by feedback? (3 ways)
*** Objective
- TRH is inhibited by high T3 levels
- TRH receptors are reduced in number by high T3/T4 levels
- TSH translation and release is reduced by high T3/T4
How are thyroid hormones transported in the blood?
*** Objective
The majority of T3 and T4 is bound to carrier proteins when circulating in the blood
- Thyroid-binding globin
- Transthyretin
- Albumin
Why don’t thyroid hormones freely flow through the blood?
*** Objective
This is because they are hydrophobic and it increases the half-life of the hormones to be transported by a carrier protein (by preventing them from being cleared by the kidneys)
What do we call thyroid hormones that are not bound to carrier proteins?
Biologically active hormones that are in the “free” form
What process did we talk about before that converts T4 to T3?
Deiodination
What are the major sites of deiodination?
Liver and kidney
What are the three types of deiodination enzymes?
*** Objective
- Type I
- Type II
- Type III
Describe type I deiodinase enzymes
*** Objective
Type I
- Primary enzyme involved in the production of circulating T3
- Also a major source of T3 in peripheral tissues
- Also produces rT3
Describe type II deiodinase enzymes
*** Objective
Type II
- Converts T4 to T3
- Important enzyme in tissues that generate T3 locally from T4 in the circulation, rather than just getting T3 from the circulation
- This is the case for pituitary and hypothalamic cells
Describe type III deiodinase enzymes
*** Objective
- Considered to be the MAJOR physiological terminator of thyroid hormone action in the peripheral tissues
- Converts T4 to rT3 and T3 to T2, both of which are inactive
- This means that type II inactivates both T4 and T3
What is the importance of sulfation in the metabolism of thyroid hormones?
*** Objective
Sulfation increases the solubility of thyroid hormones and may facilitate their removal in bile and/or urine
What role does glucuronidation play in thyroid hormone metabolism?
*** Objective
Glucuronidation
- Occurs in the liver
- Increases the water solubility of thyroid hormones
- Facilitates elimination in bile
How do thyroid hormones stimulate the basal metabolic rate?
*** Objective
Receptors for thyroid hormones are found in virtually all tissues, so it has a widespread effect
They increase the basal metabolic rate by increasing the transcription of Na/K- ATPase - this is responsible for most of the increased metabolism
What are some other effects that thyroid hormones have on the body other than an increase in metabolism?
*** Objective
- Increased cardiac output
- Increased carbohydrate metabolism
- Increased lipid metabolism
- Increased bone turnover
- Increased erythropoietin production
- Increased gut motility
- Multiple endocrine effects
What are the general consequences of HYPERthyroidism?
*** Objective
- excessive heat production
- nervousness
- insomnia
- increased heart rate
- weight loss
- increased appetite
What is Grave’s disease?
*** Objective
An autoimmune disease that is characterized by auto-antibodies which bind to the TSH receptor, making it constituently active
The release of thyroid hormone is therefore done regardless of need
What are the general consequences of HYPOthyroidism?
*** Objective
- increased sensitivity to cold
- decreased basal metabolic rate
- lethargy
- weight gain without increased caloric intake
What is Hashimoto thyroiditis?
*** Objective
An autoimmune disease that is characterized by auto-antibodies for one of several things…
- Thyroid peroxidase
- Thyroglobulin
- TSH receptor-blocking antibodies
- Other
This leads to decreased production and/or secretion of the thyroid hormones
How do the thyroid hormones enter their target cells?
*** Objective
Need to know that this does NOT occur by passive diffusion through a lipid bilayer
- There is a high affinity/low capacity transport system that exists to transport the hormones
- This is an ACTIVE process that may require energy from the sodium electrochemical gradient
Describe in general terms how the thyroid receptor/retinoid X receptor complex regulates transcription in response to thyroid hormone.
*** Objective
- Thyroid hormones work by binding to receptors in the nucleus
- They often bind to DNA as heterodimers
- The other component of a dimer is often times RXR or retinoid X receptor
- Once they bind to receptors, there is a conformational change in the thyroid hormone receptor
- This leads to relaxation of chromatin and enhancement of transcription
