5 - Thyroid Hormones Flashcards by Andrea Okas

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

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What are parafollicular cells?

The cells that surround the follicles

- These cells produce calcitonin

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What is the main source of iodine?

The diet

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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.

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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

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What is meant by organification of iodine?

Incorporation of iodine into thyroglobulin is referred to as the organification of iodine

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Why is iodine needed?

Iodinated thyroglobulin molecules are coupled together to form T3 and T4 - thyroid hormones

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What enzyme is responsible for the organification of iodine?

Thyroid peroxidase

Thyroid peroxidase is a

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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

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What happens to the oxidized iodine?

I- is oxidized to I (atomic iodine)

- Iodine reacts with tyrosine residues found within a thyroglobulin molecule

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What forms from iodine and tyrosine found within thyroglobulin?

Monoiodothyronine (MIT)

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What does MIT react with?

MIT can react with another iodine to form diiodothyronine (DIT)

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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)

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Does the thyroid gland have the capacity to store hormone?

*** Objective

Yes

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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

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What does the release of T3 and T4 require?

*** Objective

Proteolysis of thyroglobulin

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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

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Which is more abundant, T3 or T4?

*** Objective

More T4 is formed than T3
Typical ratio is 5-7 T4 for every T3

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Which is the more biologically active hormone, T3 or T4?

*** Objective

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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

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About 40% of T4 is converted to T3, particularly in the liver and kidneys

How does the conversion of T4 to T3 occur?

*** Objective

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Deiodination

There are three classes of deiodinated enzymes (deiodinases)

What process accounts for thyroglobulin found in the serum?

*** Objective

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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

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Can be a sign of…

Thyroiditis
Graves disease
Thyroid malignancy

Describe how thyrotropin releasing hormone (TRH) signals thyroid stimulating hormone (TSH; thyrotropin) release.

*** Objective

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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

5 - Thyroid Hormones Flashcards

(46 cards)