M1 L4 Flashcards
1
Q
What is stress
A
A challenge to the organism that activates the autonomic nervous system or HPA axis
2
Q
what is a stress response?
A
the non-specific response of the body to any demand for change
3
Q
What produces CRH (corticotropin releasing hormone)
A
parvocellular neurons of the paraventricular nucleus
4
Q
What do corticotropes in the anterior pituitary do?
A
Corticotropes in the anterior pituitary express CRH-R & make adrenocorticotrophic hormone (ACTH)
The gene for POMC (proopiomelanocortin) is expressed in corticotropes.
Corticotropes produce the POMC protein.
Inside corticotropes, POMC is cleaved (cut) into smaller pieces by enzymes.
One of those pieces is… ACTH!
5
Q
What produces vasopressin? Specific
A
Magnocellular neurons of the supraoptic nucleus (SON) & paraventricular nucleus (PVN)
6
Q
What is ACTH synthesized from?
A
pro-opiomelanocortin (POMC)
7
Q
What does ACTH do?
A
main job is to stimulate the adrenal glands and produce cortisol (stress hormone)
- Cortisol feeds back to inhibit ACTH from the pituitary
8
Q
What 3 active proteins can POMC be processed into?
A
ACTH, a-MSH, B-endorphins
9
Q
What 3 things is the Hypothalamus-pituitary-adrenal axis regulated by?
A
- negative feedback
- circadian rhythms
- stressors (physiological and emotional)
10
Q
What hormones does the adrenal cortex make?
A
- Mineralocorticoids (e.g. aldosterone)
- Glucocorticoids (e.g. cortisol)
- Androgens (e.g. DHEA, androstenedione)
11
Q
What does the production of glucocorticoids and mineralocorticoids require?
A
21- hydroxylase & 11beta-hydroxylase
12
Q
What is the starting molecule for all steroid hormones?
A
Cholesterol.
13
Q
What hormone is the primary glucocorticoid in humans?
A
cortisol
14
Q
What is the pathway to cortisol starting from cholesterol?
A
Cholesterol → Pregnenolone → 17α-Hydroxy Pregnenolone → 17α-Hydroxyprogesterone → 11β-hydroxylase. → Cortisol.
15
Q
Which enzyme converts 11-deoxycortisol to cortisol?
A
11β-hydroxylase.
16
Q
Which enzyme is involved in the final step of aldosterone synthesis?
A
Aldosterone synthase.
17
Q
How do we get to Mineralocorticoids (e.g. aldosterone)?
A
cholesterol -> progestogens -> glucocorticoids -> mineralocorticoids
18
Q
How do we get to Glucocorticoids (e.g. cortisol)
A
cholesterol -> progestogens -> glucocorticoids
19
Q
How do we get to Androgens (e.g. DHEA, androstenedione)?
A
cholesterol -> progestogens -> androgens
20
Q
What would happen if glucocorticoid production were compromised?
A
not enough cortisol being made which leads to many more issues of its own
21
Q
Whats happening in this pic?
A
You can’t convert 17-hydroxyprogesterone → Deoxycortisol
This means no cortisol is produced
22
Q
what is Congenital Adrenal Hyperplasia
A
group of inherited genetic disorders that affect the adrenal glands
23
Q
what is Congenital Adrenal Hyperplasia caused by
A
Most commonly caused by mutations in enzymes that convert progestogens to glucocorticoids
24
Q
Symptoms of Congenital Adrenal Hyperplasia?
A
Hypoaldosteronism –> salt balance “salt-wasting”
Hypocortisolism –> stress response
Excess androgen production –> masculinization
25
Treatment of Congenital Adrenal Hyperplasia
providing replacement glucocorticoid, mineralocorticoid, extra salt
modulating the HPG axis by delaying puberty to allow for bone growth, modulating androgen or estrogen receptor signaling
26
What is Addisons disease? aka Primary Adrenocortical Insufficency
condition where the adrenal glands don’t produce enough of certain essential hormones
27
What is addisons disease caused by?
autoimmune destruction of the cortex --> both aldosterone and cortisol are deficient.
28
Symptoms of cortisol deficiency?
poor response to stress
hypoglycemia caused by reduced gluconeogenic activity
29
Symptoms of aldosterone deficiency?
- K+ retention (hyperkalemia), due to lower K+ loss in the urine --> disturbs cardiac function
- Na+ depletion (hyponatremia), due to urinary loss of Na+ --> reduces blood volume & lowers blood pressure (hypotension).
30
Another symptoms of addisons disease?
Hyperpigmentation due to excessive ACTH
* The adrenals can't make cortisol →
So no negative feedback on the pituitary →
So the pituitary thinks the body still needs more cortisol →
It keeps cranking out tons of ACTH
31
What system is the adrenal medulla part of?
part of the sympathetic nervous system
32
What does adrenal medulla produce?
Catecholamines (epinephrine and norepinephrine)
33
What is the adrenal medulla activated by?
* how activated?
Activated by sympathetic nervous in response to stress
* CNS → preganglionic cholinergic neurons → adrenal medulla directly
34
Chromaffin cells
* what do
* where are
* make epinephrine (and some norepinephrine and dopamine)
* line in adrenal medulla
35
break down the catecholamine biosynthesis pathway
Phenylalanine → Tyrosine → L-Dopa → Dopamine → Norepinephrine → Epinephrine
36
What are Adrenergic Receptors
proteins on cell surfaces that respond to epinephrine and norepinephrine
37
What are the 2 categories of adrenergic receptors?
alpha and beta
38
What do alpha receptors have a high affinity for?
α1 & α2 greater sensitivity to NE
39
What do beta receptors have a high affinity for?
β1 binds almost exclusively to E
40
What are the 3 main types of Alpha and beta adrenergic receptors?
- α1 & α2 greater sensitivity to NE
- ß2 bind almost exclusively to E
41
Which receptor does chromaffin mainly work with?
ß2 bc they bind to epinephrine and she likes that
42
What does aldosterone do?
Increases blood pressure, reabsorption of sodium and secretion of potassium
43
What does vasopressin do?
Increases blood pressure
44
what does epinephrine do?
Increases blood pressure, blood sugar levels, increased heart rate, cardiac contractility, relaxation of smooth muscle in the airways. Reduces glucose uptake by tissues other than the brain.
45
What does cortisol do?
Increases blood glucose via gluconeogenesis. Reduces glucose uptake by tissues other than the brain. Increases lipolysis to use fat as an energy source in other tissues to conserve glucose for the brain. Anti-inflammatory and immunosuppressive effects. Suppresses reproduction
46
What activates mineralocorticoid receptors?
activated by cort and aldosterone in low and high concentrations
47
What affinity do mineralocorticoid receptors (MRs) have?
high affinity - (they bind tightly, even when cort levels are low)
48
For mineralocorticoid receptors where do they express?
expression restricted to hippocampus, central nucleus of the amygdala (CeA), lateral and medial
septum (LS and MS)
* means that mineralocorticoid receptors (MRs) are only made (or mostly made) in specific brain areas
49
What are the type 1 receptors?
mineralocorticoid receptors (MRs)
50
What are the type 2 receptors
glucocorticoid receptors (GRs)
51
What are glucocorticoid receptors (GRs) activated by?
only when cort is high
52
What affinity do mineralocorticoid receptors (MRs) have?
Low affinity (need high cort levels to activate)
53
For glucocorticoid receptors where do they express?
* 2 locations
Nearly ubiquitously expressed
* Paraventricular nucleus (PVN)
* Anterior pituitary
54
Which feedback will mediate the negative feedback of the HPA axis?
GRs help regulate negative feedback of the HPA axis, reducing cort production once it gets high
55
Explain this diagram
* what type of dimer does each receptor form
Cort will bind to the GR and MR receptors
Receptors form:
* GR/MR heterodimers
* GR or MR homodimers
These bind to GREs (glucocorticoid response elements) in DNA
Typically slow transcriptional changes
56
What area of the brain expresses both MR and GR?
the hippocampus
57
How do glucocorticoids affect memory performance?
A moderate amount of stress can enhance memory, but too little or too much cortisol impairs it.
* too much cortisol will shrink the hippocampus neurons - too much GR.
58
What is being blocked from being made here
blocks 11β-hydroxylase → less cortisol is made.
59
Explain this experiment:
Metyrapone blocks 11β-hydroxylase → less cortisol is made.
* Result: glucocorticoid synthesized, recall is worse
Hydrocortisone added = synthetic cortisol, replaces the cortisol that metyrapone blocked.
* Result: Memory performance improves, goes back to placebo levels.
60
At what point does stress become harmful?
1) Too much stress triggers the body to produce more cortisol
2) Cortisol binds to glucocorticoid receptors (GRs) in the brain.
3) too much cortisol for too long causes Overactivation of GRs (they're being constantly stimulated)
This overactivation can lead to dysfunction in brain areas like:
* Hippocampus (memory)
* Prefrontal cortex (decision making, focus)
* Amygdala (emotion, anxiety)
61
How does the U-shaped curve and expression of stress hormone receptors in the hippocampus explain test performance in response to stress? Include the receptors, their affinities for stress hormones, and how they are engaged by low or high stress hormone levels
This describes how performance (like memory or test-taking) changes with different levels of stress.
Type 1 (MR) receptors will be activated by low or high levels of cort/aldosterone. These help with baseline cognitive function, attention, and memory. Low affinity.
Type 2 (GR) receptors will be activated by high levels of cort. Involved in stress response and shutting down the HPA axis. high affinity
* Low Stress → Only MRs activated
* Moderate Stress → Both MRs + GRs activated
* High Stress → Excess GR activation (performance crashes)
62
explain the dimerization in the 3 stress levels:
Low stress: homodimerized MRs
Ideal stress: some
heterodimerization, plus MR & GR homodimers
High stress: shift to more
heterodimerization overall
* Different dimerizations → different gene expressions
63
What 3 factors does the brain regulate access to glucocorticoids? (how it protects itself from too much stress hormone)
1) corticosteroid binding globule (CHG)
2) multiple drug resistance P-glycoprotein (MDRpG)
3) 11b-hydroxysteroid dehydrogenase (11 HSD)
64
explain how corticosteroid binding globule (CHG) regulates glucocorticoid access?
binds natural glucocorticoids in the brain, making them unavailable
65
explain how multiple drug resistance P-glycoprotein (MDRpG) regulates glucocorticoid access?
* where located
* when effective
located at the BBB, actively transports synthetic steroids and some natural steroids like cortisol out of the brain
* very effective at low doses, but not when cortisol is at high levels
66
explain how 11b-hydroxysteroid dehydrogenase (11 HSD) regulates glucocorticoid access?
converts cortisol into cortisone - which is highly inactive
67
Name strategies to reduce the effects of cortisol in the brain.
1) CBG (bind cortisol)
2) MDRpG (move cortisol out)
3) 11B-HSD (inactivate cortisol)
4) down regulate receptors of cortisol (cortisol antagonists bind to the receptor instead)
5) inactivate enzyme that makes
6) low stress environment
68
You are informed that a patient
has an inactivating mutation in the gene that encodes for the enzyme 17α-hydroxylase.
a. Mark on the steroid synthesis chart where this mutation is. As a
consequence, which steroid
hormone(s) will build up in excess
(red x)
17α-hydroxylase converts precursors into cortisol and sex hormones (like androgens and estrogens). Without it, the pathway gets blocked, and precursors back up.
You will have an excess in pregenolone and progesterone
* also excess glucocorticoids and mineralocorticoids
69
If the enzyme 17α-hydroxylase is not working, what will not get made?
Normally, 17α-hydroxylase converts:
pregnenolone and progesterone into the OH versions which then makes Cortisol and Androgens and estradiol
but if blocked it cant do that
70
What doesn't work in this pathway when someone has Congenital Adrenal Hyperplasia?
CAH is 21-hydroxylase deficiency
* this means we cannot convert all the way to aldosterone so that decreases
* You also can’t make cortisol → ACTH rises → adrenal hyperplasia
* there is a build up of androgens in CAH bc if 21-hydroxylase is not working - then cortisol cant be made. this turns on the neg feedback in the hypothalamus --> they tell pituitary to release ACTH which acts on the adrenal cortex to stimulate production of more steroid hormones. THEN it gets stuck at 21 agains so they take a diff route into the androgen-making side of the steroid pathway
71
Would you expect a patient with the 17alpha mutation to exhibit the same side-effect profile of Congenital Adrenal Hyperplasia? Why or why not?
CAH is 21-hydroxylase deficiency
but in 17 alpha patient, 21 hydrozylase and 11B are still functional. so you would not expect the same side-effects
72
Name 3 characteristics of addisons disease:
1) aldosterone deficiency
2) cortisol deficiency
3) ACTH overproduction
4) hyperpigmentation of skin/gums
73
What mediates epinephrine and norepinephrine effects?
G protein coupled receptors
74
You wake up late for an exam. The very first stress hormone has immediate effects on your physiology (heart racing, freaking out) is BLANK く The hormone responsible for the rise in blood pressure that occurs while you're quickly getting ready is BLANK ~ , and the hormone that will make your hair fall out if you do this many times and too often is BLANK く
You wake up late for an exam. The very first stress hormone has immediate effects on your physiology (heart racing, freaking out) is EPINEPHRINE く The hormone responsible for the rise in blood pressure that occurs while you're quickly getting ready is VASOPRESSIN ~ , and the hormone that will make your hair fall out if you do this many times and too often is CORTISOL く
75
