The Thyroid Gland :) Flashcards
Briefly describe the key steps in thyroid hormone synthesis.
Thyroglobulin is synthesized on the rough ER and the Golgi of thyroid follicle cells and then extruded across the apical membrane into the follicular lumen.
Iodine enters the follicular cell across the basal membrane via active cotransport with Na+. The I- is then oxidized just under the apical membrane to I2 by thyroid peroxidase (inhibited by propylthiouracil (PTU) and organified (combined with tyrosine moeities of thyroglobulin) to form DIT and MIT.
The DIT and MIT combine as either MIT-DIT (T3-active) or DIT-DIT (T4-inactive). (high levels of I- inhibit organification [Wolff-Chaikoff effect])
After the coupling reactions occur, thyroglobulin contains T4, T3, and leftover MIT and DIT. This iodinated thyroglobulin is stored in the follicular lumen as colloid until the thyroid gland is stimulated to secrete its hormones (e.g., by TSH).
bonus- when stimulated, colloid is endocytosed and carried via microtubules to the basal membrane. En-route, the thyroglobulin is hydrolyzed to T3 and T4. The T3/T4 is then released into circulation.
What effect do perchlorate and thiocyanate have on thyroid hormone function and how?
There are several competitive inhibitors of Na+-I−
cotransport including the anions thiocyanate and
perchlorate, which block I− uptake into follicular
cells and interfere with the synthesis of thyroid
hormones.
Is the Na-I cotransporter an active or passive pump/channel?
Active. Iodine is moving against its chemical and electrical gradient into the follicular cells.
Describe the action of thyroid hormones on cells.
Thyroid hormones act on virtually every organ system
in the human body: Thyroid hormones act
synergistically with growth hormone and somatomedins
to promote bone formation; they increase basal
metabolic rate (BMR), heat production, and oxygen
consumption; they alter the cardiovascular and
respiratory systems to increase blood flow and oxygen
delivery to the tissues; and they stimulate maturation of the CNS.
Growth- Growth formation, bone maturation.
CNS- maturation.
BMR- ^ Na+-K+ ATPase, ^ O2 consumption, ^ Heat production, ^ BMR.
Metabolism- ^ Glu absorption, ^ glycogenolysis, ^ gluconeogenesis, ^ lipolysis, ^ Protein synthesis and degradation (net catabolic).
Cardiovascular- ^ cardiac output
Describe how T3/T4 are transported in the blood stream.
Most T4 and T3 circulates bound to
thyroxine-binding globulin (TBG). Smaller amounts
circulate bound to T4-binding prealbumin and albumin.
Still smaller amounts circulate in the free, unbound
form. Because only free thyroid hormones are physiologically
active, the role of TBG is to provide a
large reservoir of circulating thyroid hormones, which
can be released and added to the pool of free
hormone.
How is T4 activated by target cells?
The major secretory product of the thyroid
gland is T4, which is not the most active form of thyroid
hormone. This “problem” is solved in the target tissues
by the enzyme 5′ iodinase, which converts T4 to T3 by
removing one atom of I2. The target tissues also convert
a portion of the T4 to reverse T3 (rT3), which is inactive.
Essentially, T4 serves as a precursor for T3, and the relative amounts of T4 converted to T3 and rT3 determine
how much active hormone is produced in the target
tissue
Define the factors and list the specific pathways that regulate thyroid hormone synthesis.
Major control of the synthesis and secretion of thyroid
hormones is via the hypothalamic-pituitary axis.
Thyrotropin-releasing hormone (TRH) is
secreted by the hypothalamus and acts on the thyrotrophs
of the anterior pituitary to cause secretion of
thyroid-stimulating hormone (TSH). TSH then acts on
the thyroid gland to stimulate the synthesis and secretion
of thyroid hormones as well as stimulating growth and overall activity of the thyroid gland.
TSH binds to a membrane receptor on the basal surface of follicular cells which is coupled to adenylyl cyclase via a Gs protein. Activation of ad. cyc. generates cAMP, which serves as a second messenger for TSH.
**The TSH receptor on the follicular cells can also be activated by thyroid-stimulating immunoglobulins,
which are antibodies to the TSH receptor. When these immunoglobulins bind to the TSH
receptor, they produce the same response in thyroid
cells as TSH: stimulation of thyroid hormone synthesis
and secretion and hypertrophy and hyperplasia
of the gland (i.e., hyperthyroidism- Graves disease).
T3/T4 provide negative feedback on both the production of TSH in the anterior pituitary as well as the production of TRH in the arcuate nucleus of the hypothalamus.
Dopamine and somatostatin both inhibit TSH production by cells of the anterior pituitary.
Describe the course of a T4 molecule once it reaches its target tissue until it has had its terminal effects on the target cell.
T4 reaches target cell. Conversion of T4 to T3 by 5′-iodinase. Once T3 is produced inside the target cells, it enters the nucleus and binds to a nuclear receptor. The T3-
receptor complex then binds to a thyroid-regulatory
element on DNA, where it stimulates DNA transcription.
The newly transcribed mRNAs are translated, and
new proteins are synthesized. These new proteins are
responsible for the multiple actions of thyroid hormones.
Other T3 receptors located in ribosomes and mitochondria mediate posttranscriptional and posttranslational events.
BONUS: In most tissues, Na+-K+ ATPase
synthesis is induced, which leads to increased
oxygen consumption, BMR, and heat production.
How does the CV system keep up with the increased O2 demands of the peripheral tissues stimulated by T3?
Increased O2 delivery to the tissues is possible because thyroid hormones produce an increase in cardiac output and ventilation. The increase in cardiac output is the
result of a combination of increased heart rate and
increased stroke volume (increased contractility).
These cardiac effects are explained by the fact that
thyroid hormones induce the synthesis of (i.e.,
up-regulate) cardiac β1-adrenergic receptors. Recall
that these β1 receptors mediate the effects of the
sympathetic nervous system to increase heart rate
and contractility. Thus, when thyroid hormone
levels are high, the myocardium has an increased
number of β1 receptors and is more sensitive to
stimulation by the sympathetic nervous system.
Describe the cellular response to changes in thyroid hormone levels.
HYPERthyroid: ^ BMR, ^ carbohydrate metabolism (no change in blood glu), ^ protein metabolism (muscle wasting), ^ lipid metabolism ( decr. serum cholesterol), ^ body heat
HYPOthyroid: The opposite of hyperthyroid effects (no change in blood glu)
This does NOT describe hyper/hypothyroidism, as a condition. Simply a generalized increase in TH levels for a period of time.
