M1 Flashcards
classes of hormones
-
peptides: small mol of AA
- nonapeptides: 9 AA
- decapeptides: 10 AA
-
proteins: more complexity ➔ made from DNA via txl/tsl
- TSH, FSH, LH, insulin, glucagon, PRL
-
monoamines: made from AA tyrosine ➔ terminal amine + aromatic ring
- NE, EP, dopamine
-
steroids: made from CHO
- hydrophobic
- intracellular recdeptors
- estradiol, testosterone, progesterone, cortisol, aldosterone
hormone transport
hydrophilic hormones
- water soluble ➔ easy to travel in blood
- cell-membrane receptors
hydrophobic hormones
- not water soluble ∴ must be bound to specific carriers/transporters to travel through blood
- globulins
- SHBG, TBG, albumin (most abundant)
- intracellular receptors
hormone receptors
cell membrane receptors
-
GPCRs: 7 transmembrane passes
- G-protein is closely associated but not bound
- binding always extracellular
- binding causes conformational changes
- activates second messengers
- RTK receptor tyrosine-kinase (insulin)
- cytokine receptors (prolactin, GH)
intracellular receptors ➔ nuclear receptor superfamily
-
steroid receptor family form homodimers & are located in cytoplasm
- corticoid receptor (adrenal gland hormones)
- androgen receptor
- progesterone receptor
-
thyroid receptor family form heterodimers w/ retinoic acid receptor & are located in nucleus
- estrogen receptor (hybrid ➔ can form homo & heterodimers)
- Vit D receptor
- thyroid receptor
- retinoid acid receptor
GPCR pathways
second messenger cAMP
- Gs ⍺ subunit = functional
- β & 𝛾 subunits = regulatory
- inactive when bound to β & 𝛾 subunits
- adenylyl cyclase converts ATP ➔ cAMP
-
cAMP activates PKA
- short-term effects: phosphorylates substrates outside nucleus
- long-term effects: PKA crosses nuclear envelope & finds & activates CREB to find CRE (cAMP response element = short sequences/regions of DNA w/ complementary portions for binding & txr/tsl)
- most efficient: short-term available for immediate use & synthesize more for storage for immediate release upon next signal
- ACTH, FSH
second messenger IP3 & Ca
- Gq ⍺ subunit
-
phospholipase C converts PIP2 ➔ IP3 & DAG
- IP3 released in cytoplasm & travels to ER where Ca is stored ➔ mobilizes intracellular Ca
- Ca activates calmodulin (CaM) ➔ activates CaM kinase
- DAG stays in membrane & activates PKC
- GnRH
second messenger cAMP
second messenger IP3 & Ca
nuclear receptor superfamily
- main mechanism of action for hydrophobic hormones that bind to intracellular receptors is via transcription/translation ∴ longer response
- nuclear receptor hormones diffuse through PM
steroid receptor family form homodimers & are located in cytoplasm
- corticoid receptor
- androgen receptor
- progesterone receptor
thyroid family receptors form heterodimers w/ retinoic acid & are located in nucleus
- estrogen receptor (hybrid ➔ can form both homo & heterodimers)
- vit D receptors
- thyroid receptors
- retinoic acid receptors
nuclear receptor action
steroid receptor
- steroid diffuses through PM
- receptor held together by heat shock protein (HSP) ➔ “chaperone” stabilizing protein
- HSP dissociates when steroid hormone binds to receptor
- receptor carries into nucleus & finds to & binds HRE
thyroid receptor: hormone is carried by carrier protein into nucleus b/c receptor is already bound to HRE in DNA
neurophypophyseal neurons
PVN: paraventricular nucleus contains magnocellular & parvocellular neurons
- AVP
- OT
- (CRH - part of parvocellular/adenohypophysis sysyem)
&
SON: supraoptic nucleus contains only magnocellular neurons
- 80-90% produces AVP
hypophyseotropic neurons
contain parvocellular neurons
Arc: arcuate nucleus
&
POA: pre-optic nucleus
PVN: paraventricular nucleus (contains both magnocellular & parvocellular)
infundibulum
anatomical stalk connecting hypothalamus & pituitary gland
hypothalamamic hypophyseal tract
bundle of magnocellular axons from hypothalamus to neurohypophysis
median eminance
functional connection stalk btwn hypothalamus & adenohypophysis
hypophyseal portal system
capillary bed where parvocellular neurons release hormones to reach adenohypophysis
magnocellular neurons
- larger cell bodies
- longer axon projections that extend to the neurohypophysis
- AP opens Ca v-gated channels ➔ Ca influx facilitates fusion of hormone vesicles with PM to release hormone
parvocellular neurons
- smaller cell body
- short axon projections that terminate in the hypophyseal portal system
- secrete hypophysiotropic hormones that regulate secretion of adenohypophysis hormones
neurohypophysis
posterior pituitary
- where magnocellular neurons from PVN & SON end & release hormones
- glandular portion
- secretion of 2 nonapeptides: vasopressin (AVP) & oxytocin (OT)
- vasopressin = water control ➔ ↑ water reabsorption in kidneys (also regulates BP but same effect)
- oxytocin = milk release from mammary glands, contractions, & maternal behaviors
adenohypophysis
anterior pituitary
- cellular portion
- somatotrophs secrete GH
- lactotrophs secrete PRL
- thyrotrophs secrete TSH
- gonadotrophs secrete FSH & LH
- corticotrophs secrete ACTH
pineal gland
- tryptophan ➔ serotonin ➔ melatonin ➔ control of circadian rhythms & reproductive cycles for seasonal breeders
- synthesis of melatonin in response to light/dark stimuli
AVP/OT precursor molecule
- required for proper protein folding
-
neurophysin = critical for proper protein folding
- propressophysin ➔ AVP + neurophysin II + glycopeptide
- prooxyphysin ➔ OT + neurophysin I
- precursor packed in secretory granules in Golgi apparatus & cleaved during axon transport
AVP fx
vasopressin
-
regulation of water ➔ ↑ # of aquaporins & translocation to apical membrane of principal cells of the collecting duct cells of kidney
- most important fx
- V2R in kidney: GPCR that uses a Gs ⍺ subunit
-
osmoreceptors in cells detect ratio of solids to liquids
- blood osmolarity = amount of solutes in blood ➔ ↑ osmolarity (>280mOSM) = less liquid/more solutes ➔ activates osmorecdeptors
- dehydration = main signal ➔ ↑ osmolarity & cell shrinks in size ➔ osmoreceptors can sense shrinked MP
- short-term resposne: APQ2 translocation to apical membrane of principal cells to let water re-enter cells
- long-term response: ↑ expression of APQ2 & APQ3 in principal cells
-
BP maintenance ➔ vasoconstriction of vessels
- V1R = GPCR that uses a Gq ⍺ subunit
-
baroreceptors in aorta (aortic arch receptors) & carotids (carotid sinus receptors)
- stmiulation of AVP by ↓ BP/BV
- increase expression of ACTH receptors
AVP action in kidneys
V2R = Gs ⍺ subunit GPCR
- AVP binds to V2R ➔ adenylyl cyclase converts ATP ➔ cAMP ➔ activates PKA
- PKA phosphorylates APQ2 ➔ activates in cytosol & allows it to transport to apical membrane for water re-entry
- water now accumulating in cell moves through APQ3 & APQ4 channels in basolateral membrane into interstitial space
- APQ2 & APQ3 = targets of AVP
- APQ4 is permanent
diabetes insipidus
- consequence of AVP deficiency
- indiv cannot concentrate urine ➔ diluted urine, no smell or color
- neurogenic: caused by mutations that inactivate AVP production ➔ issue is in PVN & SON nuclei
- nephrogenic: caused by mutations in the V2R or APQ2 genes in the kidneys
-
AVP deficiency model: brattleboro rat has a genetic mutation in neurophysen II ➔ cannot fold AVP protein properly ∴ cannot synthesize AVP
- neurogenic
- symptoms: polyuria/polydipsia
- urine = 80% total fluids
- 20-30x increase in urine V than control
- ↓↓↓ osmolarity compared to control
OT fx
- parturition: involved in uterine contractions during stage 2 (fetal expulsion)
- in lactation: CRITICAL for milk letdown during lactation
- critical in parental bonding & maternal behavior
OT action
OTR = GPCR associated with Gq ⍺ subunit: phospholipase C converts PIP2 to IP3 & DAG ➔ IP3 mobilizes intracellular Ca ➔ activates CaM ➔ activates CaM kinase & DAG activates PKC to stimulate smooth muscle contraction
in parturition:
- stage 1: fetal development
- progesterone maintains uterine quiescence during pregnancy ➔ blocks contractions (& estrogen)
- towards end of preg: ↑ estrogen & ↓ progesterone
- estrogen stimulates expression of OTR in myometrium & synthesis of OT
- stage 2: fetal expulsion
- OT stimulates contractions in uterine fundus
- mechanoreceptors sense pressure on cervix ➔ send signals through spinal cord to PVN & SON nuclei ➔ ⊕ feedback signals release of more OT ➔ ferguson reflex
in milk letdown:
- OT acts on myoepithelial cells surrounding epithelial cells
- suckling ➔ mechanoreceptors in breasts ➔ afferent signal through spinal cord ➔ stimulation of magnocellular neurons for pulsatile OT release ➔ pumping action in alveoli ➔ maximum secretion of milk
- w/out OT: cannot secrete milk ➔ no other hormone stimulates myoepithelial cell contraction in alveoli
all steroids come from ___________ via ___________
CHO via steroidogenesis
- steroid skeleton = 3 cyclohexane rings + 1 cyclopentane ring
- steroidogenesis involves changes in hydroxylation & removing C
CHO
- CHO biosynthesis: acetyl-CoA + acetoacetyl-CoA
- maintains fluidity of PM
- precursor mol for all steroid hormones
main source/site of CHO synthesis
- hepatocytes in liver ➔ de novo sunthesis
- animals must ingest ➔ cannot make enough
- CHO in PM interacts w/ GCPR & ion pumps that have specific ion binding sites for CHO ➔ pumps are deactivated if missing/depleted
CHO most abundant in
brain myelin sheaths
CHO transport in blood
via LDL (low-density lipoprotein): CHO bound to the OH group of a long chain fatty acid (has CHO + other lipids)
genes involved in steroidogenesis
- there are no genes for steroids but there are genes for proteins that cleave the steroids along the pathway
- 57 P450 enzymes ∴ 57 CYP genes
- 7 mitochondrial
- 50 SER
CYP11A1 gene encoding P450scc
location:
fx:
goal:
located in mitochondria
fx: 10,10-desmolase
goal: CHO side chain cleavage ➔ first step in steroidogenic pathway
CYP17A1 gene encoding protein P450c17
location:
fx:
goal:
locted in SER
fxs:
- 17⍺-hydroxylase (in zona fasciculata)
- 17,20-lyase (in zona reticulata)**
goals:
- 17⍺-hydroxylase: pregnenolone ➔ 17⍺-hydroxypregnenolone
- 17,20-lyase: 17⍺-hydroxypregnenolone ➔ DHEA**
CYP21A2 gene encoding protein P450c21
location:
fx:
goal:
located in SER
fx: 21-hydroxylation
- progesterone ➔ 11-deoxycorticosterone
- 17⍺-hydroxyprogesterone ➔ 11-deoxycortisol
- most common mutation for congenital adrenal hyperplasia (CAH)
CYP11B1 gene encoding protein P450c11β
location:
fx:
goal:
located in mitochondria of ZG cells
fx: 11β-hydroxylation
goal: 11-deoxycortisol ➔ cortisol
CYP11B2 gene encoding protein P450aldo
location:
fx:
goal:
located in mitochondria of zg cells
fx: 18-hydroxylation
goal: biosynthesis of aldosterone
3β-hydroxysteroid dehydrogenase (3β-HSD)
- located in SER
- pregnenolone ➔ progesterone
- 17𝛼-pregnenolone ➔ 17𝛼-progesterone
- DHEA ➔ androstenedione
17β-hydroxysteroid dehydrogenase (17β-HSD)
- located in SER
- androstenedione ➔ testosterone
- DHEA ➔ androstenediol
5⍺-reductase
- located in SER
- testosterone ➔ dihydrotestosterone
sulfokinase
- DHEA ➔ DHEA sulfate (DHEAS)
- weak androgen ➔ less affinity for androgen receptor
- works to maintain DHEAS storage
aldosterone pathway in steroidogenesis
CHO
↓ CHO desmolase (CPY11A1➞ P450scc)
pregnenolone
↓ 3β-HSD
progesterone
↓ 21-hydroxylase (CYP21A2 ➞ P450c21)
11-deoxycorticosterone
↓ 11β-hydroxylase (CYP11B1 ➞ P450c11)
corticosterone
↓ aldosterone synthase (CYP11B2 ➞ P450aldo)
aldosterone**
cortisol pathway in steroidogenesis
CHO
↓ CHO desmolase (CPY11A1 ➞ P450scc)
pregnenolone
↓ 17𝛼-hydroxylase (CYP17A1 ➞ P450c17)
17⍺-hydroxypregnenolone
↓ 3β-HSD
17⍺-hydroxyprogesterone
↓ 21-hydroxylase (CYP21A2 ➞ P45c21)
11-deoxycortisol
↓ 11β-hydroxylase (CYP11B1 ➞ P450c11)
cortisol**
androgen pathway in steroidogenesis
CHO
↓ CHO desmolase (CPY11A1 ➞ P450scc)
pregnenolone
↓ 17𝛼-hydroxylase (CYP17A1 ➞ P450c17)
17⍺-hydroxypregnenolone
↓ 17,20-lyase (CYP17A1 ➞ P450c17)
DHEA
↓ 3β-HSD
androstenedione
↓ 17β-HSD
testosterone**
zones of the adrenal gland
**cortex: steroid hormones ➔ derived from mesoderm of abdominal wall
- zona glomerulosa ➔ aldosterone synthesis
- mineralocorticoids ➔ aldosterone
- “minerals” ➔ regulating mineral balance (salt) in kidneys
- virtually no MC2R ➔ non-responsive to ACTH
- mineralocorticoids ➔ aldosterone
- zona fasciculata ➔ glucocorticoids ➔ cortisol synthesis
- cortisol fx: ↑ glucose levels in blood via gluconeogenesis in liver
- majority of cortex
- most responsive to ACTH ➔ slight hypertrophy & hyperplasia
- zona reticularis ➔ androgen synthesis
- dehydroepiandosterone (DHEA)
- important for females
- responsive to ACTH
medulla: non-HPA hormones
- epinephrine
- norepinephrine
- derived from neuroectoderm: ANS/SNS**
CHO uptake & initiation of steroidogenic pathway
- start with LDL
- internalized by cell via LDL receptor
- inside cell: LDLR + LDL is endocytosed ➔ receptor is reparated from the LDL in the endosome & LDL (CHO ester = bound to fatty acid) is hydrolyzed by CHO esterase that releases free CHO
- LDLR recyled back to PM
- StAR protein finds free CHO & carries to mitochondria where steroidogenesis begins
- steroidogenesis starts in mitochondria ➔ goes to SER ➔ back to mitochondria for adrenal hormone synthesis**
parvocellular hypothalamaic nuclei
PVN
- CRH ➔ corticotroph cells secrete ACTH ➔ act on adrenal gland
- TRH ➔ thyrotroph cells secrete TSH ➔ act on thyroid gland
- AVP produced by magnocellular neurons & secreted by neurohypophysis to regulate water & BP & also produced by parvocellular neurons as a 2º stimulatory signal for ACTH release ➔ maximizes response**
ARC
- GnRH ➔ gonadotrophs cells secrete LH & FSH ➔ act on gonads
- GHRH ➔ somatotroph cells secrete GH ➔ act on liver
- SST: somatostatin ➔ inhibitory: ⊖ regulator of GH
- dopamine ➔ inhibitory: ⊖ regulator of PRL
POA
- GnRH
VIP: prolactin-releasing factor ➔ lactotroph cells secrete PRL
adenohypophysis hormone main fxs
positive actions ➔ stimulate glands
ACTH:
- synthesis of adrenal hormones
- ↑ in adrenal weight (due to ↑ activity)
PRL
- mammary growth
- milk synthesis
- thermoregulation
- behavioral
- immune-related
TSH
- synthesis of TH
- thyroid weight (active cells enlarge)
FSH
- follicle growth
- spermatogenesis
- estradiol production ➔ conversion of androgens to estrogens
GH
- tissue growth
- metabolic effects
LH
- ovulation
- testosterone production
ACTH action
- ACTHR = MC2R: melanocortin 2 receptor
- expressed in zona fasciculata & zona reticularis
- effects
- ↑ glucocorticoids (main response)
- ↑ DHEA
- ↑ adrenal weight via hypertrophy (increased secretory activity ➔ cells swell) & hyperplasia
- ↑ medullary hyperplasia ➔ ↑ release of EPI & NEPI
- ↑ expression & translocation of LDLR to membrane to facilitate LDL internalization of CHO for steroidogenesis
- intracellular activation by PKA:
- CHO esterase
- Star activated
- P450scc
- ↑ gene expression of CHO esterase, StAR protein, & P450scc**
ACTH response to hypoglycemia
- stimulates PVN in hypothalamus to release CRH ➔ enters portal system
- stimulates corticotrophs in adenohypophysis to release ACTH into systemic circulation
- stimulates adrenal gland to produce cortisol in the zona fascicularis
- stimulates liver gluconeogenesis
- prolonged stress response surpasses circadian rhythm
- prior high-dose synthetic glucocorticoid administration abolishes stress response
- ↑↑ adrenal hormone levels act as negative feedback to HPA axis**
ACTH precursor
proopiomelanocortin (POMC)
- mol have diff biological activity depending on cleavage location
- 𝛼MSH ➔ food intake, metabolic rate
- β-endorphin ➔ endogenous opioid
- response depends on site of hormone synthesis & receptor
-
MC1R in melanocytes & leukocytes of skin ➔ stimulates melanin prod
- prevents/limits further UV penetration
- repairs DNA damage
- MC2R for ATCH in adrenal cortex ➔ cortisol synthesis
- MC3R in CNS ➔ feed intake regulation
-
MC1R in melanocytes & leukocytes of skin ➔ stimulates melanin prod
congenital adrenal hyperplasia (CAH)
- lack of cortisol prod during fetal development ➔ lack of ⊖ feedback for HPA axis
- results from a defficiency in an enzyme in the cortisol pathway (mutations in the CYP21A2 gene that encodes P450c21 that converts progesterone ➔ 11-deoxycorticosterone & 17⍺-hydroxyprogesterone ➔ 11-deoxycortisol)
- excess of ACTH & overstimulation of adrenal gland cause:
- adrenal hyperplasia
- excess prod of adrenal androgens ➔ pathway will be overactivated but the only direction it can go is towards androgens (masculinization = problematic for females)
systemic effects of cortisol excess
brain:
- depression
- psychosis
endocrine:
- ↓ TSH, LH, & FSH release
- ↓ GH secretion
eye: glaucoma
carbohydrate/lipid metabolism:
- ↑ hepatic glycogen deposition
- ↑ peripheral insulin resistance
- ↑ gluconeogenesis
- ↑ free fatty acid production
- overall diabetogenic effect
adipose tissue distribution: promotes visceral obesity
bone & calcium metabolism:
- ↓ bone formation
- ↓ bone mass & osteoporosis
skin/muscle/connective tissue:
- protein catabolism/collagen breakdown
- skin thinning
- muscular atrophy
immune system:
- anti-inflammatory action
- immunosuppressant
growth & development: ↓ linear growth
cardiovascular/renal:
- salt & water retention
- hypertension
GI tract: peptic ulcers
glucocorticoid regulation of BG
- most tissues in body express glucocorticoid receptor
- glucocorticoid effects counteract insulin: insulin inserts glucose channels to facilitate glucose uptake by tissues
- cortisol ↑ BG by inhibiting uptake in peripheral tissues & by stimulating gluconeogenesis
- “glucose sparing effect”
- catabolic effects to break apart gluconeogenesis substrates
- muscle: stimulates myostatin ➔ proteolysis to release AA
- adipose tissue: stimulates hormone-sensitive lipase (HSL) ➔ lipolysis to release FA & glycerides
- liver: stimulates PEPCK & glucose-6-phosphatase: gluconeogenic enzymes**
targets of cortisol in BG in homeostasis
- stimulates gluconeogenesis
- glucose-6-phosphatase
- phosphoenolpyruvate carboxykinase (PEPCK)
- stimulates glycogen synthase
- inhibits glycogen phosphorylase
- Activates lipolysis: hormone-sensitive lipase (HSL) breaks down fatty acids
- ↓ protein synthesis
- stimulates myostatin to break down muscle fibers**
systemic effects of chronic synthetic glucocorticoids (hyperadrenocorticism)
- ↑
- PEPCK, myostatin, lipase
- circulating AA
- BG (↑ 50%)
- ↓
- body weight ➔ change in the pattern of fat distribution: visceral fat accumulation
- muscle mass
- endogenous cortisol
- removing synthetic glucocorticoid supplementation could send indiv into hypoadrenocorticism b/c HPA axis was strongly inhibited by ⊖ feedback ➔ system doesn’t resume as quickly as rx is halted
GCR action
held together by heat shock protein (HSP) until GC binds, then dissociates
clinical uses of glucocorticoids
- allergic dermatitis
- transplant recipients
- inflammatory diseases ➔ potent inhibitors of immune system
inflammatory response
- inflammation = results of 1st line of defense (innate)
- initiated on site of antigen contact
- clinical signs:
- swelling ➔ edema from blood
- redness
- heat ➔ tons of metabolic activity generates heat
- pain
- tumor ➔ enlarged site b/c extra cells migrate to area
- loss of fx ➔ tissue busy fighting injury
regulation of immune system by glucocorticoids
2 levels of immune defense:
* innate - 1st line
* antigen presenting cells ➔ macrophages, dendritic cells, neutrophils
* phagocytosis of antigens at site of injury
* antigen processing & presentation
* production of pro-inflammatory cytokines: interleukins (IL) & tumor necrosis factors (TNF)
-
acquired - 2nd line
- attract other immune cells
- build immune memory
- steroids act at beginning of inflammatory cascade to block entire pathway
- NSAIDs block specific parts of the pathway but not other ➔ attenuate & minimize response but don’t completely stop it
aMSH is found in
- intermediary lobe of pituitary
- Arc
- keratinocytes (MC1R)
A: GnRH (females)
B: CRH + AVP
C: TSH
D: dopamine
E: GnRH
F: GHRH
G: SST (somatostatin)
A: corticotrophs
B: thyrotrophs
C: gonadotrophs
D: somatotrophs
E: lactotrophs
A: ACTH
B: TSH
C: PRL
D/E: LH & FSH
F: GH
parvocellular neurons
A: POA
B: PVN
C: Arc
what hormone stimulates OT receptors & OT
estrogen
precursor for oxytocin
prooxyphysin
precursor for vasopressin
propressophysen (neurophysen II + glycopeptide)
glomerulosa
hormone B: pregnenolone
enzyme E: 3β-HSD
hormone C: progesterone
enzyme G: P450c21
enzyme H: P450c11
enzyme J: P450aldo
fasciculata
- enzyme B: P450c17
- hormone D: 17⍺-hydroxypregnenolone
- enzyme E: 3β-HSD
- enzyme H: P450c11
- hormone O: cortisol
reticularis
- enzyme C: 17,20-lyase
- hormone F: DHEA
- enzyme F: sulfokinase
- hormone J: DHEAS
- enzyme E: 3β-HSD
- hormone H: androstinedione
- enzyme D: 17β-HSD
- hormone B: pregnenolone
- enzyme E: 3β-HSD
- hormone C: progesterone
- enzyme G: P450c21
- hormone K: 11-deoxycorticosterone
- enzyme H: P450c11
- hormone M: corticosterone
- enzyme J: P450aldo
- hormone N: aldosterone
- enzyme B: P450c17 ➞ 17⍺-hydroxylase
- hormone D: 17⍺-hydroxyprenenolone
- hormone E: 17⍺-hydroxyprogesterone
- hormone L: 11-deoxycortisol
- hormone O: cortisol
- enzyme C: P450c17 ➞ 17,20-lyase
- hormone F: DHEA
- hormone H: androstinedione
- enzyme D: 17β-HSD
- hormone I: testosterone
- hormone G: androstinediol
