Lecture 9 - ACTH and Glucocorticoids- the regulators of stress responses Flashcards
HPA axis: what is it, what do each of the parts release, and what do these secreted hormones do?
Hippocampus - pituitary gland - adrenal gland
The hippocampus releases corticotrophin-releasing hormone (CRH) which activates the pituitary gland
Pituitary gland - releases adrenocorticotrophic hormone which activates the adrenal gland
Adrenal gland - releases cortisol which affects the body
Glucocorticoids: what is an example of a difference between humans and rats/mice?
- Cortisol in humans
- Corticosterone in rats and mice
Hypothalamus and pituitary locations
Hypothalamus sits behind the eye with the pituitary gland just below it, connected by the infundibulum, a stalk of nerves and blood vessels connecting the posterior parts
The pituitary gland sits just below the optic chiasm and just above the sphenoid sinus
Infundibulum
Pituitary stalk
Hormones produced by the adrenal gland: where are they produced, what are the types, and what are examples of them?
Cortex:
* Glucocorticoids - cortisol
* Mineralocorticoids - aldosterone
* Sex steroids - testosterone/oestrogen
Medulla:
* Epinephrine
* Norepinephrine
Glucocorticoid effects: liver, adipose tissue, muscle, immune system, bone, brain, cardiovascular system, kidney, skin, and fetus
- Liver - Increases blood glucose - stimulates gluconeogenesis and glycogenolysis
- Adipose tissue - increase lipolysis
which go to the liver - Muscle - decreases protein synthesis and increases protein metabolism
- Immune system - anti-inflammatory and immunosuppressive effects
- Bone - decrease osteoblasts and stimulate bone resorption
- Brain - affect memory and sleep patterns and mood
- CV system - increase blood pressure and cardiac output
- Kidney - increase water diuresis and glomerular filtration rate, minor effect on sodium retention and potassium
excretion - Skin - inhibit keratinocyte proliferation and
differentiation and reduce sebum production - Fetus - required for organ maturation particularly the lung
Glucocorticoids: what are their effects on the liver?
Liver - Increases blood glucose - stimulates gluconeogenesis and glycogenolysis
Glucocorticoids: what are their effects on the adipose tissue?
Adipose tissue - increase lipolysis
which go to the liver
Glucocorticoids: what are their effects on the muscles?
Muscle - decreases protein synthesis and increases protein metabolism
Glucocorticoids: what are their effects on the immune system?
Immune system - anti-inflammatory and immunosuppressive effects
Glucocorticoids: what are their effects on the bones?
Bone - decrease osteoblasts (inhibiting bone formation) and stimulate bone resorption
Glucocorticoids: what are their effects on the brain?
Brain - affect memory and sleep patterns and mood
Glucocorticoids: what are their effects on the cardiovascular system?
CV system - increase blood pressure and cardiac output
Glucocorticoids: what are their effects on the kidneys?
Kidney - increase water diuresis and glomerular filtration rate, minor effect on sodium retention and potassium
excretion
Glucocorticoids: what are their effects on the skin?
Skin - inhibit keratinocyte proliferation and
differentiation and reduce sebum production
Glucocorticoids: what are their effects on the fetus?
Fetus - required for organ maturation particularly the lung
Glucocorticoids: how do they affect insulin?
They result in glucose production from the liver - initially suppressing insulin to raise blood glucose levels
Once blood glucose levels have been raised, this acts back on the pancreas, causing insulin secretion which causes the recruitment and storing of glucose in tissues such as muscles, supplying them with the glucose they need for the stressful situation they are in
Is the immunosuppressive nature of glucocorticoids always bad?
No, it is only bad when it is uncontrolled
Stopping inflammation is important in not having excessive inflammation and damage to tissues and the body
Gluconeogenesis
Producing glucose from non-carbohydrate sources (proteins etc)
Glycogenolysis
Breaking down glycogen into glucose
Lipolysis
Metabolic process that breaks down fat stores into energy-rich fatty acids and glycerol
Water diuresis
Increased urine flow caused by decreased reabsorption of solute-free water in the collecting ducts
Mechanisms controlling the HPA axis
- Circadian - ACTH/cortisol vary on time
- Pulsatile -
- Stress - promotes CRH release
Circadian rhythm: what is it, how is it different to a diurnal rhythm, and how can it be related to the HPA axis?
The natural 24-hour cycle of physical, mental, and behavioural changes that occur in the body
Diurnal rhythm - 24-hour cycle synchronized to and dependent on an external cue
Circadian rhythm - 24-hour cycle based on internal, cyclic events (synchronised to but not dependent on an external cue)
Diurnal Rhythm - ACTH and cortisol levels are highest at ~06.00 and lowest at ~00:00
Pulsatile control of HPA axis hormones
Episodes of release last from 1 to 3 hours
* 7 to 8 episodes per 24 hours.
* They are not evenly distributed, there are fewer episodes at night
* Reason for episodic release of ACTH and cortisol is not clearly understood but recent computational modelling suggests timeframe of molecular events controls it
HPA axis negative feedback
Cortisol inhibits the secretion of ACTH from the pituitary as well as CRH from hippocampus
Factors controlling the HPA axis: what are they and how do they affect the HPA axis?
- Interleukins - stimulate HPA axis which in turn suppresses the immune system as glucocorticoids exhibit their effects
- SME - very strongly activates the pituitary gland, causing high levels of ACTH production
- CRH - stimulates ACTH weakly alone but strongly with AVP, suggesting a synergistic effect
- AVP - stimulates ACTH weakly alone but strongly with CRH, suggesting a synergistic effect
Factors controlling the HPA axis: what are they and how do they affect the HPA axis? (ER)
Inhibitors of CRH:
* L-dopa
* Serotonin
* VIP
* ANP
* GABA
Factors directly affecting the pituitary:
* PACAP
* LIF
* IL-1/2/6
* Oncostatin M
* Catecholamines
SME: what is it, where is it obtained from, and what does it do?
Stalk median eminence - tissue obtained from the infundibulum, so contains the factors leaving the hypothalamus
Greatly activates the pituitary gland, causing high levels of ACTH production
CRH: what is it, what is it synthesised by, where is it found, what does it do, what is its structure, and what is its receptor?
Corticotrophin Releasing Hormone
Synthesised by hypothalamus
- Skin, immune cells, and adrenal gland in small amounts
Stimulates ACTH synthesis
41 amino acid peptide
- CRH-R1 (accounts for all HPA activity)
- CRH-R2
AVP: what is it, what does it do, and how does it affect the HPA axis?
Arginine vasopressin - ADH
Controls water reabsorption
Simulates ACTH weakly alone but strongly with CRH, suggesting a synergistic effect
ACTH production: what is the gene it originates from, how may it be regulated, and what proteins are integral to its processing?
POMC (Pro-opiomelanocortin) gene
May be regulated at POMC transcription, POMC mRNA translation, or POMC protein processing
Prohormone convertase 1
POMC gene: what are the potential products from processing?
- ACTH - adrenocorticotrophic hormone
- βLPH - beta lipotrophin
- N-POC - N-terminal pro-opiocortin
- JP - Joining peptide
- MSH- melanocyte-stimulating hormone
- CLIP- corticotrophin-like intermediate peptide
- βEP- beta-endorphin
POMC processing: what are the reactions and what enzymes are key in the processing?
POMC —(PC1)–> βLPH + pro-ACTH
pro-ACTH —(PC1)—> JP + N-poc + ACTH
N-poc —(PC2)—> γ₃MSH
ACTH —(PC2)—> αMSH
βLPH —(PC2)—> βEP + βMSH
Regulation of the POMC gene
POMC transcription promotors:
* CRH - CRHR activation, adenylyl cyclase activated, cAMP produced, PKA activated, cAMP response element binding protein activated, ChREBPB activated, promoting POMC transcription
* CRH - CRHR activation, MAPK pathway activated, downstream AP-1 promotes POMC transcription
* AVP - V1b (receptor) activated, cAMP produced, aiding the CRH activation
* AVP - V1b activated, PKC activated, unknown further mechanisms
POMC transcription inhibitors:
* Glucocorticoids - bind to GR which translocates into the nucleus and inhibits POMC transcription
* Glucocorticoids - GR activated which then inhibits K⁺ channel, preventing the influx of Ca²⁺ which causes ACTH release
Regulation of the POMC gene (ER)
- ERK/Nur77 pathway
- K⁺ regulation controls membrane potential and promotes calcium release as K⁺ are released, Ca²⁺ influx promotes ACTH secretion
Regulation of ACTH secretion: what are the two types of secretion and what are the mechanisms behind them?
Constitutive secretion:
* Immature secretory granule containing unprocessed POMC which is constantly secreted to maintain baseline POMC levels even without an external stress signal
Regulated secretion:
* Vesicles containing ACTH that has had the proper processing are produced from the Golgi and secreted in response to a secretagogue (ie CRH)
ACTH: what receptor does it act on?
Melanocortin 2-Receptor (MC2-R)
αMSH: what is it, why does its mutation in children result in obesity, what is it produced by, and what other adverse effects may it have?
α melanocyte-stimulating hormone
- αMSH acts back on MC4R and MC3R receptors in the hypothalamus to inhibit hunger
- If mutated, αMSH may fail to be produced and therefore children feel constant hunger and become obese
PC2 cleaving ACTH
In excess amounts, it may cause pigmentation as it can also bind to MC1R/MC5R receptors
αMSH: what are the two receptor systems it can act on?
MC4R/MC3R in the hypothalamus - results in satiety and reduced hunger
MC1R/MC5R in the skin - results in pigmentation
Cortisol: what is it produced from, what hormone stimulates its synthesis, what does it act on, at what times are its levels highest/lowest, and how does it travel around the body?
The zona fasciculata of the adrenal gland
ACTH from the pituitary gland
Sugar and stress
- Negative feedback on the pituitary gland and hippocampus - inhibiting CRH and ACTH synthesis and secretion
- The body’s glucocorticoid receptors
Highest - 6:00
Lowest - 00:00
Circulating cortisol is bound to a carrier protein - corticosteroid binding globulin (CBG)
CBG: what is it, what does it do, how is it affected in certain diseases, and why is it so important?
Corticosteroid binding globulin
Binds circulating cortisol (responsible for binding 90% of cortisol and 60% of aldosterone)
CBG levels increased by diseases including
hyperthyroidism and diabetes, which will change the bioavailability of cortisol as only free cortisol is active
Cholesterol synthesis and secretion in adrenal gland cells
- Cholesterol is taken into the mitochondria through the StAR protein
- It is then converted to pregnenolone
- Pregnenolone moves into the ER where it is converted to 11-deoxycortisol which then moves back into the mitochondria where it is converted into cholesterol and can then be released from the cell
Why does this happen - who knows
Cholesterol synthesis and secretion in adrenal gland cells (ER)
More in-depth image in the lecture
