Week 4 L3 Functions of Adrenal Cortex Flashcards
What is the order of the layers of the adrenal cortex?
Remember GFR: glomerulosa, fasciculata, reticularis (from outer to inner)
What does the zona glomerulosa produce?
Aldosterone
What does the zona fasciculata produce?
Cortisol
What does the zona reticularis produce?
Androgens: DHEA, androstenedione
What is the relationship between cortisol and epinephrine in the adrenal gland?
Blood washes first through the zona fasciculata and becomes saturated with cortisol. That blood then reaches the adrenal medulla, where high cortisol concentration is necessary for stimulation of the PNMT enzyme that produces epinephrine from norepinephrine
What is cholesterol synthesized to as the rate-limiting step of steroid biosynthesis? What is the enzyme?
Makes pregnenolone, by cholesterol side chain cleavage enzyme (CYP11A1)
In the zona glomerulosa, what steroid biosynthesis enzyme is present and what enzyme is missing, and because of this it is able to produce its particular hormone?
It has CYP11B2 (aka aldosterone synthase), but is missing CYP17 (17 alpha hydroxylase). So it follows down its pathway to produce aldosterone
In the zona fasciculata, what steroid biosynthesis enzyme is present and what enzyme is missing, and because of this it is able to produce its particular hormone?
It has CYP17 (17 alpha hydroxylase) and CYP11B1, but no CYP11B2. Also, activity of 17,20 lyase is low so it falls down the cortisol pathway and doesnt produce sex steroids.
In the zona reticularis, what steroid biosynthesis enzyme is present and what enzyme is missing, and because of this it is able to produce its particular hormone?
It has CYP17 (17 alpha hydroxylase) and the 17,20 lyase activity is higher than in the fasciculata, so it produces DHEA and androstenedione
What enzyme converts pregnenolone to progesterone? (also converts 17-OH pregnenolone and DHEA)
3-Beta Hydrogenase (or 3β-HSD for hydroxysteroid dehydrogenase)
What enzyme converts pregnenolone or progesterone into 17-OH pregnenolone or 17-OH progesterone?
CYP17, activity of 17 alpha hydroxylase
What enzyme converts 17-OH pregnenolone and 17-OH progesterone into sex steroids, and what are their products?
17,20 Lyase. Converts 17-OH pregnenolone -> DHEA, while 17-OH progesterone -> androstenedione
What enzyme is used to convert progesterone to DOC (deoxycorticosterone? It also converts 17-OH progesterone into 11-deoxycortisol
21 Hydroxylase (CYP21A2)
What enzyme converts deoxycorticosterone (DOC), and into what product?
CYP11B2 (a 11β-Hydroxylase function) converts DOC -> corticosterone
What enzyme converts 11-deoxycortisol, and into what product?
CYP11B1 (a 11β-Hydroxylase), converts it into cortisol
What enzyme converts corticosterone, and into what product?
Again, CYP11B2 (but the 18-Hydroxylase function) converts it into 18-OH corticosterone
What enzyme converts 18-OH corticosterone, and into what product?
Again, CYP11B2 (but the 18-Oxydase function), converts it into Aldosterone
What happens to androstenedione after it is produced in the zona reticularis?
It is converted to other steroids in the periphery (testis, ovary)
What protein helps cholesterol to be transported into the mitochondria of cells that synthesize steroid hormones?
StAR (Steroidogenic Acute Regulatory Protein)
Is there storage of steroid hormones?
No, they are produced and secreted on-demand. However, there is storage of cholesterol esters in lipid droplets that are converted back to cholesterol (by cholesterol esterase) then made into steroids
What is the main regulatory hormone of steroid synthesis? What is its mechanism?
ACTH. Activates ACTH MC2 receptor -> cAMP increase -> PKA -> StAR phosphorylated -> cholesterol transport into mitochondria increased. ACTH also leads to proliferation of zona fasciculata
What are the effects of Angiotensin II on hormone synthesis?
Angiotensin II -> AT1 receptor -> calcium signal -> PKC -> StAR phosphorylated -> cholesterol transport into mitochondria increased
When a person is given glucocorticoids for a long time and then taken off of them, what may occur as a result of negative feedback?
While taking the glucocorticoids, negative feedback caused the adenohypophysis to produce less ACTH, and in its absence the zona fasciculata may become atrophied. Thus, when glucocorticoid supplementation ends, the body may not have the ability to produce enough cortisol to maintain normal levels.
What protein does cortisol bind to most of the time for transport? What percentage of cortisol is bound to this protein? What is the significance of this binding?
Transcortin (CBG) - 90% of cortisol is bound to it. Has high binding affinity, and increases the half-life of cortisol to about 70 minutes
What percentage of cortisol is bound to albumin?
5-7%
What protein does aldosterone bind to, and how is the affinity? What is the significance of this?
Aldosterone binds to albumin with low affinity-binding. Leads to a shorter half-life than cortisol (about 20 minutes)
What is the difference in secretion rate between cortisol and aldosterone? What is the difference between their concentrations?
Cortisol has 100 x more secretion, but 1000 times difference in concentration
How much cortisol is secreted in a day?
20 mg / day
How much aldosterone is secreted in a day?
0.15 mg / day
What is the plasma concentration of cortisol?
0.1-0.5 micromolar
What is the plasma concentration of aldosterone?
0.1-0.3 nanomolar
In humans, what is the main glucocorticoid? What is the main mineralocorticoid?
GC = cortisol, MC = aldosterone
What 2 types of receptors (broadly) can be targeted by corticosteroids?
Cytosolic and membrane receptors
What is an example mentioned in lecture where the corticosteroid receptor is a transcription factor?
For the glucocorticoid receptor (GR), which is a dimer with heat shock protein 90. It binds to its ligand and then dissociates from HSP90, and then it can upregulate or downregulate expression of proteins
What is the effect of glucocorticoids on the NF-κB pathway?
The NF-κB is a transcription factor which regulates cytokines involved in inflammation. Without stimulus, NF-κB is inhibited by its IκB subunit, which breaks free and degrades if there is inflammatory stimuli. Glucocorticoids are anti-inflammatory in that they stimulate transcription of IκB and bind to NF-κB to prevent it from transcribing inflammatory factors
What are the two GPCRs (7 transmembrane receptors) of membrane receptors by glucocorticoids?
Gs (activating cAMP) and Gq (calcium signal)
Regarding the glucocorticoid receptor type I (mineralocorticoid receptor, MR), what is the effect of its “preceptor specificity?”
(yes the naming for these receptors is confusing)
The cytosolic type I receptors bind to cortisol and aldosterone with equal affinity (so can still be called glucocorticoid receptors). However, these cells also contains 11-β-HSD2, which inactivates cortisol into cortisone. This enzyme has no effect on aldosterone, and so more aldosterone can target the MR type I receptor than cortisol, despite the 1000 x larger cortisol concentration.
What are the main effects of aldosterone?
Reabsorption of sodium in the collecting duct, potassium excretion, Na+/K+ ATP-ase activity increase, and activation of proton pump in intercalated cells (Summary: increases body’s Na+; decreases body’s K+ and H+)
What effect does aldosterone have on the citric cycle enzymes?
It increases their expression, matches an increased ATP demand
What is the effect of ANP on aldosterone? Of ACTH?
ANP -> inhibition of aldosterone production. ACTH -> increased responsiveness of cells to aldosterone
What is the effect of angiotensin II on aldosterone? Why does this occur?
Stimulates its production (via AT1 receptor, Gq). Occurs due to blood volume decrease, arterial pressure decrease, sympathetic tone increase, and low sodium intake.
