Glucocorticoids-Cortisol Flashcards
How to remember which steroids are created where in the adrenal cortex?
G: salt
F: sugar
R: sex
Where does glucocorticoid get its name?
From raising plasma glucose levels
What do glucocorticoids regulate?
Immune Developmental Body fluid homeostasis Metabolism Arousal and cognition Decreases cannabinoid CB1 receptor
What do glucocorticoids cause when they bind GR?
Regulates epidermal growth factor reducing its activity which in turn reduces creation of arachidonic acid (therefore COX2)
Where is the glucocorticoid hormone cortisol formed?
In the zona fasciculata
What turns stored cholesterol into free cholesterol in the zona fasciculata?
Cholesterol ester hydrolyase
What encodes cholesterol side-chain cleavage enzyme desmolase?
CYP11A1 gene
What binds HDL on the adrenal cortex cell membranes?
SRB1 encoded by SCARB1 gene
Pathway for how cholesterol is converted to cortisol?
Cholesterol-> Pregnenolone-> Progesterone-> 17-hydroxyprogesterone-> 11-deoxycortisol-> cortisol
In the absence of CYP11B1 what pathway is used instead of cholesterol-> cortisol?
Progesterone-> 11-deoxycorticosterone (DOC)-> corticosterone
Why is DOC significant?
DOC acts as a weak mineralocorticoid and elevated levels lead to hypertension
Key cytochrome P-450 enzyme involved in cortisol synthesis?
17alpha-hydroxylase
What triggers synthesis and release of cortisol?
Paraventricular neurons (hypothalamus)
What transports cortisol in the blood?
Corticosteroid-binding globulin aka transcortin
Circulating half-life of cortisol?
90 minutes
What receptor does CRH work through and review the intracellular pathway?
G-protein coupled receptor-> AC-> cAMP->PKA-> Ca-> ACTH exocytosis
What receptor does ACTH bind to in the adrenal cortex?
MC2R (melanocortin-2 receptor)
What is the specificity of mineralocorticoids and glucocorticoids to receptors?
Glucocorticoids have a higher affinity than mineralocorticoid receptors and they share receptors (nonspecificity)
What prevents the nonspecificity for glucocorticoids to mineralocorticoid receptors and the significance of this?
11-hydroxysteroid dehydrogenase type 2 in mineralocorticoid target cells converts GC to a less active form that allows mineralocorticoids to have higher affinity to the receptors; it allows mineralocorticoids to bind to receptors (if absent then GC would always bind)
Aside from 11-hydroxysteroid dehydrogenase type 2, what ensure that MC effects can be mediated in the presence of GC?
Aldosterone (MC) dissociates more slowly from receptors than GC so it is less easily displaced
What does 11beta-HSD1 and 11beta-HSD2 do respectively?
HSD1: converts cortisone to cortisol
HSD2: converts cortisol to cortisone
How do glucocorticoids ready the innate immune system?
- ) TLR induction
- ) NLRP3 inflammasomes and P2Y2R induction
- ) Increasing IL-6 and IL-8
What pro-inflammatory transcription factors do glucocorticoid receptors repress?
AP-1
NF-kappa B
Mnemonic to remember cortisol function?
BIG FIB
BIG FIB:
Increase: blood pressure, insulin resistance, gluconeogenesis
Decrease: fibroblast activity, inflammatory and immune response, bone formation
Summary of action of glucocorticoids?
Hyperglycemia: increase gluconeogenesis and Glycogenolysis
Free FA and AA production
Catecholamine release
Anti-inflammatory/immunosuppressive
Mineralocorticoids long-term stress response:
- ) Retention of Na and water by kidneys
2. ) Increased blood volume -> increased blood pressure
Glucocorticoids long-term stress response:
- ) Proteins and fats broken down and converted to increased blood glucose
- ) Immune system suppression
What is Cushing’s syndrome?
Elevated glucocorticoids long-term (cortisol)
What is Addison’s disease?
Insufficient levels of glucocorticoids
