hormone signaling pathways Flashcards
what is an example of endocrine signaling
epinephrine
what is an example of paracrine signaling
testosterone
receptors involved in hydrophilic hormone signaling
GPCRs and RTKs
cytoplasmic receptors exists in an inactive complex with ___ and upon binding to hormone ___ dissociates. The hormone receptor complex goes to the nucleus and binds the __ ___ ___ in promoter region of specific genes
HSP90, HSP90. hormone response element (HRE)
nuclear receptors
already present in nucleus bound to DNA
-hormone signal activates the complex and allows for interactions with additional proteins
hydrophilic signal molecules: aa derived
melatonin, epinerphrine, norepinephrine, dopamine, histamine, serotonin
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hydrophilic signal molecules from lipid metabolsim
acetylcholine
hydrophilic signal molecules: polypeptides
TSH, cytokines, insulin, glucagon
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what is the second messenger for epinephrine
GPCR
what kind of receptor is insulin
receptor tyrosine kinase
hydrophilic meds vs lipophilic meds, which has a long half life, which has short
hydrophilic has short, lipophilic has long
what exchanges GDP for GTP and what subunit of g protein does this occur on
GEF and on alpha subunit of G protein
how does the G protein go back to inactive GDP form
has intrinsic GTPase activity which is accelerated by GAP
what does Gs stimulate
adenylate cyclase and increase in cAMP and activation of PKA
what does Gt stimulate
hydrolysis of cGMP by cGMP PDE triggered by light in vision
what does Gi do
inhibits adenylate cyclase so no cAMP and no PKA
how is PKA activated
PKA has 2 Regulatory subunits and 2 catalyic subunits
- when cAMP binds to regulatory subunits it causes the complex to dissociate
- free catalytic subunits phosphorylate target proteins
how is cAMP turned off
and what inhibits this enzyme
it is hydrolyzed into AMP by phosphodiesterase (PDE)
-caffeine inhibits this
Gq signaling steps
1) signal binds, GDP swapped for GTP on alpha subunit
2) a-GTP activates PLC to convert PIP2 to IP3 and DAG
3) IP3 binds and releases Ca2+ stores from SR
4) increased intracellular Ca2+ causes PKC to go to plasma membrane where it is activated by DAG and phosphorylates target proteins
5) calcium also binds calmodulin which activates myosin light chain kinase and CaM kinase
6) MLC kinase phosphorylates myosin light chains and causes smooth muscle contraction
- CaM kinase phosphorlyates target proteins to alter activities
epinephrine binds to what type of GPCR protein
all adrenergic receptors: a1,a2,B1,B2,B3
what effects does epinephrine have on broncial and intestinal smooth muscle
relaxation
epinephrine binding alpha2 adrenergic receptor is associated with what G protein and what effect
Gi and constriction of SM
epinephrine binding to B adrenergic receptor is associated with what G protein
Gs and relaxes bronchiole and intest smooth muslce
- increases glycogen and TG breakdown
- increases glycolysis in musle
- causes contraction of heart
histamine binds ___ receptor coupled with ___ G protein
-effect?
H2, and Gs
-bronchoconstriction and allergic rxns
a1 adrenergic receptor is linked to what G protein
Gq
epinephrine and CREB
epinephrine binds to B Gs receptor eventually leads to activation of PKA which phosphorylates CREB
-CREB-P goes to nucleues and binds CRE which activates gene expression
how is inactive insulin stored in body
as a hexamer with zinc in center connected to polypeptide via histadine
the active form of insulin is a __
monomer
regulation of insulin secretion
glucose comes in through GLUT then phosphorylated by glucokinase
- participates in glycolysis and enters TCA which makes ATP and shuts of K+ ATPase
- causes depolarization of membrane so Ca2+ comes in
- calcium causes fusion of granules to membrane and release into the bloodstream
insulin signaling RAS dependent pathway
1) insulin binds alpha subunit, RTK phosphorylates itself and B subunit
2) this recruits IRS-1 which then gets phosphorylated by RTK
3) GRB-2 binds phosphorylated IRS-1
4) this activates RAS then MAP kinase
5) leads to increased txn of glucokinase
6) increases glucose uptake and glycogen synthesis
insulin signaling RAS-independent pathway
1) insulin binds alpha subunit, RTK phosphorylates itself and B subunits
2) IRS-1 recruited and phosphorylated
3) P13 kinase binds phophorylated IRS-1
4) PI3-kinase activates phosphorylates phosphoinositides to make PIP3
5) PIP3 stimulates recritment of PKB to membrane and activates it
6) eventually leads to increased GLUT4 to PM;
7) actiavtion of glycogen synthase (inhibits glycgoen synthase kinase)
insulin resistance
increased phophorlyation of serine via ser/thr kinase instead of tyrosine in the insulin receptor and IRS
-this inactivates IRS1 and 2 leading to degradation
what are Ser/Thr kinases activated by
cytokines, free FA, DAG, inflammatory molecules
3 domains of nuclear receptors
DNA binding domain (highly conserved)
Ligand binding domain
Activation Function 1 domain
ligand binding domain is bound by what
inhibitory proteins while inactive
-ligand binding releases this
2 responses of steroid hormones
primary early response
- primary protein then shuts off early primary response and also turns on secondary response genes
where is ERa expressed
in female reproductive tract mammary gland hypothalamus endotelial cells vascular SM
where is ER-beta expressed
prostate and ovaries
both Er-a and Er-b are expressed in breast cancers but ___ is predominant form responsible for growth regulation
ERa
how does tamoxifen work
its a drug metabolized by cytochrome p450 then turns to 4-hydroxy-tamoxifen
-this raises affinity by 40X
binds receptor tight, recruits histone deacetylase 1
-stabilize nucleosome structure and prevent interaction with GTA
molecular mechanism of action of estrogen receptor
agonist binds which recruit co-activator proteins to modify chromatin structure and activate HAT
-this leads to recruitment of GTA and induces txn of proliferation
some evidence that estrogen receptor is located where?
in the cytosol, estrogen binding causes dimerization and translocation to the nuclues
