cell phys unit 4

cholesterol/C27

has many derivatives, will always turn into progesterone before anything else

C21s

progesterone, corticosterone, aldosterone, and cortisol

progesterone

can become testosterone or corticosterone

corticosterone

primary glucocorticoid from birds and rodents, can become aldosterone by adding aldehyde or cortisol by adding hydroxy group

cortisol

glucocorticoid from adrenal cortex that modulates glucose handling and is important for immune function, can interact with glucocorticoid receptors and mineralocorticoid receptors

11 beta HSD2

inactivate cortisol and make cortisone, so that aldosterone can bind instead of cortisol

11 beta HSD1

can go back and forth between corticosterone and cortisol

testosterone/C19

can be made into dihydrotestosterone with 5alpha reductase to interact with androgen receptors better, can be made into estradiol/C18 by aromatase

finastride

can block 5 alpha reductase, used to treat things like prostate cancer

letrozole

will block aromatase to prevent estradiol from being formed

vitamin D3 cholecalciferol/1,25 dihydroxycholecalciferol/1,25 D3

animal derived form, will have two additional OH groups and a double bond

vitamin D2 ergocalciferol

plant derived

thyroxine/T4

becomes T3 and reverse T3 by metabolizing an I, they are active forms

retinoic acid/vitamin A

receptor is promiscuous and will dimerize with other hormone receptors

steroid hormone receptor agonists

vitamin D3/D2, thyroxine, T3, reverse T3, retinoic acid/vitamin A

androgen receptor agonists; antagonists

testosterone, DHT, nandrolone; flutamide, enzolutamide

estrogen receptor agonists; antagonists

estradiol/clomiphene; fulvestrant, tamoxifen

progesterone receptor agonists; antagonists

progesterone; mifepristone/RU486

glucocorticoid receptor agonists; antagonists

cortisol, dexamethasone, prednisolone; mifepristone

most glucocorticoid receptors affect _ receptors

progesterone

mineralocorticoid receptor agonists; antagonists

aldosterone; spironolactone

spironolactone

will also block male androgen receptors

vitamin D3 receptor agonists; antagonists

vitamin D, maxacalcitol; ZK159222

retinoic acid receptor agonists; antagonists

retinoic acid, maxacalcitol; YCT-529 (male contraceptive)

thyroid hormone receptor agonist

T3

carrier proteins

allow for solubility, vitamin D binding protein, retinol binding protein, thyroxine binding globulin, transthyretin (TTR), sex hormone binding globulin, transcortin

thyroxine binding globulin and transthyretin (TTR)

carry thyroid hormones

sex hormone binding globulin

for steroid androgens and estrogens

transcortin

for cortisol (75% bound), lower affinity for progesterone and aldosterone (20% bound)

albumin

low affinity high capacity binding protein, will bind 50% of aldosterone and 80% of progesterone

receptor structure subunits

ligand-binding domain, inhibitory proteins, DNA binding domain, and transcription activating domain

DNA binding domain

gives specificity to interaction with DNA

transcription-activating domain

gives receptor function

common signaling mechanism for receptor

from inactive receptor to active receptor, ligand binds, inhibitory proteins come off, change in conformation causes receptor to dimerize with protein, get transcription of target genes

signaling mechanism from gland

gland secretes hormone → binds to carrier proteins in circulation with some bound and some free → free ligand crosses cell layers into cytosol → binds to receptor and releases inhibitory protein → dimerize and enter nucleus through nuclear pore → bind to DNA and associate with cofactors to initiate transcription → RNAs leave nucleus and cause protein synthesis → change in function

why do ligands need carrier proteins?

they are hydrophobic

multiple transcription cycles pathway

ligand activates steroid hormone receptor which dimerizes → primary proteins are synthesized → primary proteins shut off primary response genes and turn on secondary response genes → secondary response proteins are made, examples: SGK, ENaC, ROMK

coactivators/corepressors

give specificity for type of cell response

signaling via intracellular receptors is relatively _

slow, minutes to hours to days

renin-angiontensin-aldosterone system

nephrons in juxtaglomerular apparatus senses a decrease in blood pressure and renin is released → renin goes to liver turns angiotensinogen into angiontensin → ACE changes angiontensin in lungs to angiontensin II → angiontensin II goes to adrenal gland → the angiontensin receptors and GPCRs change phospholipase C activity and DAG concentration → ADH and aldosterone released → genes are transcribed to manage/retain blood volume by increasing ENaC channels for retaining Na and increasing ROMK channels for secreting K

aliskiren; enalapril; telmotran

blocks renin; blocks ACE; blocks angiontensin II receptors

eicosanoids

molecules from arachidonic acid, very hydrophobic and have no carrier proteins so usually autocrine or paracrine signaling, includes prostaglandins, thromboxanes, and leukotriene

phospholipase A1/A2

cuts diacylglycerol at glycerol backbone to make arachidonic acid

PTGS1/COX1 and PTGS2/COX2

turns arachidonic acid into prostaglandins, prostacyclins, and thromboxane

5-LOX

turns arachidonic acid into leukotrienes

PTSG1/COX 1 is a _, which means

constitutive enzyme, always expressed by certain cells

PTGS1/COX 1 functions

cytoprotection, anti-apoptotic, platelet aggregation, and vasoconstriction

PTGS2/COX 2 functions

inflammation, pain, cytoprotection, anti-apoptotic, platelet resting, vasodilation, dilation of afferent arteriole

5-LOX functions

bronchoconstriction, mucus secretion, luteolysis

almost all eicosanoid receptors are through _

G proteins

Gs pathway

PGE2 binds to EP2 (transmembrane) receptor → EP2 receptors recruit and activate Gs proteins → Ga,s activates adenylyl cyclase to produce cAMP (second messenger) → activates various pathways

Gi pathway

PGE2 binds to EP3 (transmembrane) receptor → EP3 receptors recruit and activate Gi proteins → Ga,s inhibits adenylyl cyclase production of cAMP (second messenger) → reduces cAMP-dependent pathways

TXA2 pathway

TXA2 binds to TP-beta receptor → TP-beta receptors recruit and activate Gq proteins → Ga,q activates phospholipase C by cutting off head group to produce DAG and IP3 (both can be second messengers) → activate various pathways

four cardinal signs of inflammation

rubor (redness), tumor (swelling), calor (increased temperature), and dolor (pain)

annexin A1

glucocorticoid that inhibits phospholipase A2

glucocorticoid side effects

breakdown of proteins, suppress immune response and inflammation, and promotes glucose concentration to brain

NSAIDs

blocks PTGS1/COX1 and PTGS2/COX2

NSAIDs side effects

increases oxidative damage, digestive enzymes, and increase HCl, so may cause ulcers

coxibs

blocks only PTGS2/COX2

coxibs side effects

may cause adverse cardiovascular events by increasing clotting, offset by using aspirin

aspirin

blocks COX1 more than COX2 to promote blood thinning