Final revision Flashcards
Describe the hypothalamus-pituitary- adrenal axis
What are the enzymes that are specific for each adrenal gland zone that allow them to produce their specific hormones
Z. fasciculata: none
Z. glomerulosa: aldosetrone synthase
Z. retucularis: 17, 20 lyase (DHEA-> androstenedione)
What is the first step common to all steroids?
Where does it take place?
How is it formed
The first step common to all steroids is the formation of pregnenolone from cholesterol
Takes place in the mitochondria
On inner mitochondrial membrane, P450scc (side-chain cleavase) cleaves the side chain of cholesterol to produce pregnenolone
How is cholesterol taken up into the mitochondria for steroidogenesis?
v Uptake of cholesterol is a rate limiting step and
v Regulated by StAR protein (Steroid Acute Regulatory protein)
(smooth endoplasmic reticulum)
v StAR is cAMP-inducible gene and increases in response to tropic hormones (i.e. ACTH in the adrenal gland and gonadotropins in gonads)
Cortisol can also activate __ receptor
Cortisol can also activate aldosterone receptor
How is cortisol, hypokalemia and hypertension connected?
kidney and other cell types inactivate cortisol to prevent inappropriate activation of the aldosterone receptor – when cortisol levels are too high HSD2 is overwhelmed and cortisol stimulates Na+/K+ exchange in kidney causing hypokalemia and hypertensiom
Metabolic effects of cortisol
Effects are generally opposite to insulin and similar to GH (i.e. increase in blood glucose) at the expense of protein and fat. Action depends on the target cells:
- Muscle cells, adipocytes lymphocytes: increased Catabolism
- Liver: increased Glycogen synthesis and Gluconeogenesis
- Increase of blood glucose despite the increase in glycogen storage
Anti-inflammatory effects of cortisol
- Cortisol inhibits the immune response and hence is anti- inflammatory
- Widely used to treat inflammatory conditions (i.e. rheumatoid arthritis and other immune disorders)
- Leads to atrophy of the lymph nodes and thymus (activation of apoptosis)
- Decrease in number of lymphocytes and antibody production vPatients become susceptible to infections
Cortisol and norepinephrine
- Sensitizes arterioles to the action of norepinephrine (hypertension)
- Permissive effect on the action of norepinephrine on carbohydrate metabolism (glycogenolysis → hyperglycemia)
cortisol is primarily regulated by _ hormone _
cortisol is primarily regulated by trophic hormone ACTH
Transport of circulating cortisol
- Corticosteroid Binding Globulin (CBG = Transcortin)
- Synthesized by the liver & has high affinity for cortisol
- Binds about 75 % of all cortisol in the plasma,about 10 % is “free” and 15% is bound to serum albumin
What is cushings syndrome
Increased glucocorticoid activity (cortisol excess)
What is addison disease?
Causes?
Adrenal hypofunction (cortisol deficiency)
Most commonly due to destruction of the adrenal gland by an autoimmune response
Name adrenal steroid hormones groups and functions
• Mineralocorticoids
– Affect mineral homeostasis
• Glucocorticoids
– Affect glucose metabolism and immune function
Name eicosanoid hormones common precursor
arachidonic acid
Name adrenal medulla amino acid hormones and their common function
- Epinephrine
- Norepinephrine
- Dopamine
- Often used as neurotransmitters
Are endocrine glands permanent or transient structures?
Both
– Pituitary, adrenal, pancreas are permanent
– Ovarian follicle and corpus luteum are transient
Name neurons that produce hormones
– Hypothalamus
– Posterior pituitary
– Adrenal medulla
Between which AA are disulphide bridges formed
Between cysteines
Hormones are stored in vessicles are preprohormone/ prohormone/ hormone
prohormone
Bronzing and excessive freckles are associated wiht which disease?
Addison disease
Lack of hormones increases ACTH secretion by the pituitary (removes –ve feedback)
Cortisl secretion rhytms
Cortisol secretion: maximalbetween 4-8 a.m.
GH and PRL secretion rhytm
GH, PRL maximal secretion 1h after going to sleep
Gonadotropin secretion rhythm
Released mainly at night during puberty. Released in a pulsatile fashion in adults.
Describe ectodomain
Signal binds to ectodomain (NH2 end)
Rich in cysteine residues (S-S bonds for folding).
Often glycosylated.
What are the 3 amino acids that get phosphorylated in the signalling cascade? What is the relative frequency and time of occurence of each?
- Serine, threonine, tyrosine
- Phosphorylated serines and threonines more abundant than phosphorylated tyrosines
- Tyrosines phosphorylation often occurs at the beginning of a cascade (many receptors have or induce tyrosine kinase activity)
- The phosphorylated tyrosines serve as docking sites for down stream signal proteins
What are the 2 types of Tyrosine kinase linked receptor?
Intrinsic TK activity
Rectuited TK activity
G⍺ subunits types and functions
- Gs⍺ alpha: Activates adenylate cyclase
- Gi⍺ alpha: Inhibits adenylate cyclase
- Gq⍺ alpha: Activates phospholipase C
- IP3 and DAG and Ca signaling
- Go⍺ alpha: Activates ion channels
- G12/13⍺: regulate Actin cytoskeleton
Many receptors of non-endocrine signals also act via_
Many receptors of non-endocrine signals also act via G-proteins
intrinsic TK receptor example is _
intrinsic TK receptor example is insulin receptor
Structure of a receptor with intrinsic TK activity
Hetero-tetrameric structure (2 α and 2 β chains)
Homology with the IGF-I receptor
Sequence of events after insulin binding
- Autophosphorylation of intracellular domain of receptor
- Docking and phosphorylation of IRS-1 and IRS-2 (insulin receptor substrate)
- Activation of two major signal pathways- MAPK or PI3 pathway
What are receptors with recruited tyrosine kinase activity characterized by?
Characterized by 4 alpha-helices and homology of the ectodomain (hormone binding site)
Name receptors with recruited tyrosine kinase activity
Best known are the receptors for growth hormone (GH), prolactin (PRL) and leptin
GH signaling pathways
GH has two binding sites and binds sequentially to two receptor molecules
Dimerization of the cytoplasmic regions initiates signal transduction
First step is to recruit JAK-2: phosphorylates itself, the receptor and other proteins
- Branch 1: Activation of the transcription regulatory proteins, STAT (4 isoforms)v
- Branch 2: Activation of the MAPK pathway (as insulin, but JAK2 plays the role of IRS1)
- Branch 3: Activation of PI3K pathway
Jak-stat pathway
- after jak is rectuited and dimerization occurs
- tyrosine kinase activyt is stimulated
- they phosphorylate themselves and phosphorylate the receptors
- this phosphorylation of the receptor’s cytoplasmic domain allows for recruitment of STAT (has multiple isoforms (1-5))
- stat is brough to the receptor
- JAK-2 phsophoryalyaes STAT
- phosphoryated STAT dimerize and are released from the receptor and go into the nucleus
- binds to DNA and change gene expression
Classes of NR ligands
ligands can be classified in groups:
1) classical
2) vitamins and their derivatives - Vit A and Vit D- these vitamins are lipid soluble, so these derivatives will also be lipid soluble and will bind to nuclear receptor
3) metabolic intermediates and products
Steroid vs nuclear receptors
steroids function as homodimer
Nuclear receptos function as heterodimer
two different ectodermal components of Hypothalamo-hypophyseal tract
- Rathke’s pouch: outgrowth of the buccal cavity detaches itself and becomes the anterior pituitary
- The infundibulum develops from an outgrowth of the neuroectoderm from the floor of the third ventricle. It gives rise to the pituitary stalk, the median eminence and the posterior pituitary.
Describe blood supply of anterior pituitary
- anterior pituitary is highly vascularized: capillary bed in anterior pituitary is connected to capillary bed in median eminence through portal veins
- Releasing factors are secreted into median eminence that go to pituitary
- Retrograde flow of blood allows for –ve feedback from pit. to hypothalamus
What is the name of the vein that carries hypophysiotropic hormones to anterior pituitary
portal
What is posterior pituitary made of
Posterior pituitary is composed of the nerve ending (axons) of neurons whose cell bodies are located in the hypothalamus
Oxytocin and vasopressin are produced in the_, packaged into __ which migrate to the __
(oxytocin and vasopressin) are produced in the cell bodies, packaged into granules which migrate to the ends of the axons located in the posterior pituitary
Hormones of anterior pituitary
Which receptro type is used by ?
Post-receptor intracellular signaling by G-proteins
- Trophic hormones: Gs⍺ and Gq⍺ proteins. Leads to increased Ca2+ levels and exocytosis of hormone granules.
- Inhibitory hormones: Somatostatin and dopamine act via Gi⍺ and other mechanisms.
What acts as a cricadian pacemaker
The suprachiasmatic nucleus or nuclei (SCN)
Functions of pineal gland
- Secretes melatonin (hormone of the dark)
- Induction of sleep
- Depression of reproductive activity, inhibition of ovulation and semen production in some animals –questionable role in humans
- Seasonal fluctuations may affect the timing of breeding, migration and hibernation in mammals
where are melatonin receptors foudn in the body?
Melatonin-receptors are found (almost) everywhere in the human body
Which hormones of pituitary are co-expressed/ uniqely expressed
- No unique TSH cells
- 60-70% GH+ cells express only GH
- 6-16% PRL+ cells express only PRL (sexual dimorphism-more uniquely prolactin producing cells in females, than in males )
- Both gonadotropins are co-expressed
What is the Largest portion of endocrine cells in anterior pituitary
somatotrophs
What hormones are stored in somatotrophs?
GH
Differences in genders in response to GHRH treatment
response is stronger in males than females
Somatostatin inhibits GH __ but not __
Somatostatin inhibits GH secretion but not synthesis
How do GH secretioj patterns change thorughout life
Levels fetus > child < adolescent > adult
Changes in amplitude but not frequency of pulses
Growth hormone signaling
Uses rectuited TK
JAK2 -> STAT; MAPK; PI3K
effect of suppressor of cytokine signaling (SOCS) on GHR signaling
suppressor of cytokine signaling (SOCS) inhibits GHR signaling
Growth hormone effects on growth
Direct actions: Promotion of cell differentiation
Indirect actions: Induction of IGF-I that promotes cell division and has insulin-like effects
Growth-promoting effects of GH via IGF-I
Important during childhood growth, but less during gestation and for the neonate.
IGF-I levels parallel growth rate in children
GH and IGF-I promote growth of long bones at the epiphyseal plates (proliferation of cartilage cells, i.e. chondrocytes).
Epiphyses fuse at the end of puberty and longitudinal growth ceases
Metabolic effects of GH
- In adults: optimizes body composition, physical function and substrate metabolism
- Interacts with insulin to regulate Glu, fat and protein metabolism
- Enhances lipolysis and FA oxidation – imp during fasting
- Reduces urea synthesis and excretion – Protein sparing
- Increases AA uptake and protein synthesis
- Inhibits insulin stimulated glucose uptake
- Also, GH treatment induces insulin secretion and glucose uptake
Regulation of GH release
- Balance between GHRH and somatostatin (GH release inhibiting hormone)
- Feedback control by IGF-I on pituitary and hypothalamus
- Feedback control by GH
- Metabolites:
- Increase: Hypoglycemia (e.g. produced by insulin administration) Amino acids (arginine)
- Decrease: Hyperglycemia (oral glucose), free fatty acids
Prolactin has stimilair structure to __
GH
__ and __ are essential for initiation and maintenance of milk secretion
PRL and cortisol are essential for initiation and maintenance of milk secretion
What regulates PRL gene expression
Positive: PrRP, EGF, FGF, VIP, estrogen, TRH, thyroid hormone
Negative: dopamine, endothelin, TGFb
What is required for duct system development?
Alveolar growth?
Duct: estrogen, GH, adrenal steroids
Alveolar growth: estrogen, progesterone, adrenal steroids
ACTH is derived by proteolytic cleavage of _
ACTH is derived by proteolytic cleavage of a large precursor molecule pro-opiomelanocortin (POMC)
Adrenocorticotrophin (ACTH) and related peptides
v Melanocyte stimulating hormones (MSH) -> Darkening of the skin
v Beta-endorphin - Morphine-like activity
v ACTH - Adrenal steroidogenesis
Mechanism of action of ACTH
v Binds to receptors in the adrenal gland
vActivate Gsα-protein
vEnhanced mobilization of cholesterol.
vIncreased conversion of cholesterol to pregnenolone
Control of ACTH secretion
vControlled by the hypothalamic hormone CRH
v CRH induced by stress (pain, fear, fever, hypoglycemia)
vLowest around midnight, morning peak and then declines
vCRH action is potentiated by other hormones (vasopressin)
vSubject to feedback control by cortisol
Thyrotropin (TSH) structure and recptor type used
Two protein chains (⍺ and β) Glycosylated.
Unique β-chain; Common ⍺-chain with FSH/LH
Receptor signaling via G-proteins (cAMP).
Tumors secreting _, _ or _ are most common.
vTumors secreting PRL, GH or ACTH are most common
Factors that stimulate vasopressin release
Angiotensin II
Hyperosmolarity
Decreased atrial receptor firing
Sympathetic stimulation
WHAT Can lead to diabetes insipidus of pregnancy if over-expressed
Vasopressin
Natriuretic peptides
what are they, where are they produced, where are thir receptros found
what is the effect
v Peptides that increase the excretion of H2O and Na+
v Produced in the heart muscle cells and stored in granules
v Receptors are present in the glomeruli, medullary collecting ducts of the kidney, the zona glomerulosa of the adrenal cortex and in peripheral arterioles
v Increases glomerular filtration
v Reduces blood volume and pressure
Where are sex streoids produced and which factors controll this process
v Sex steroids are mainly synthesized in the gonads (Females: estrogens and progestogens; Males: androgens) –regulated by gonadotrophins
v Adrenal cortex (mainly zona reticularis) contributes to the production of DHEAS and androstenedione – regulated by ACTH and hypothalamic CRH.
Congenital adrenal hyperplasia (CAH)
vExcessive androgen production
vMasculinization of genitalia
Adrenal medulla and _ cells are part of the _ nervous system
Adrenal medulla and chromaffin cells are part of the sympathetic nervous system
What is the stimuli of adrenal medulla to release hormones?
Preganglionic neurons release acetylcholine to stimulate medulla cells to release hormones
Hormones of the Adrenal Medulla
Catecholamines (norepinephrine (20%) and epinephrine (80%)) synthesized from tyrosine
Other hormones secretion of adrenal medulla
Granules also contain met-enkephalin and and leu-enkephalin (related to endorphins).
They are co-excreted with the catecholamines
Enkephalins may block neurotransmitters (like morphine)
act as an endogenous analgesics (runners overcoming pain and being euphoric)
effects of epineprhin
- rapidly mobilizes fatty acids as the primary fuel for muscle action
- increases muscle glycogenolysis
- mobilizes glucose for the brain by increased hepatic glycogenolysis and gluconeogenesis
- preserves glucose for CNS by decreased insulin release leading to reduced glucose uptake by muscle/ adipose
- Increases cardiac output
