Hormone Signaling Pathways Flashcards
How is cell signalling generally terminated?
by removal of signaling molecule or receptor
or attenuation/inactivation of signaling events
What is juxtacrine signaling?
signaling molecule stays attached to the secreting cell and binds a receptor on an adjacent targent cell
How is hydrophilic hormone signaling accomplished?
hydrophilic signal binds receptor at cell surface –> molecule-receptor complex initiates production of second messenger molecules –> cellular response
main receptors = GPCRs, RTKs
How do lipophilic hormones signal?
passively diffuse through plasma membrane of target cell –> bind receptor in PM or on nucleus –> acts as a transcription factor
What are the main hydrophilic hormones?
amines: histamine, SE, melatonin, dopamine, NE, epi
From lipid metabolism: Ach
Polypeptides: insulin, glucagon, cytokines, TSH
What are the main lipophilic hormones?
steroids: progesterone, estradiol, testosterone, cortisol, aldosterone, Vit D
Thyroid hormone
retinoids
What is the difference in half-lives of hydrophilic and lipophilic hormone medications?
hydrophilic = short half lives
lipophilic = long, slow acting
What are the basics of GPCR signaling?
inactive trimeric G protein –> GEF exchanges GDP for GTP –> gamma and beta leave = active –> GAP removes Pi –> inactive trimeric w/ GDP
What does a Gs receptor do?
stimulates adenylate cyclase –> cAMP –> PKA –> other proteins phosphorylated
What does a Gi receptor do?
inhibits Adenylate cyclase –> no cAMP produced
What does a Gt receptor do?
light –> GPCR –> cGMP phosphodiesterase
What does a Gq receptor do?
Gq –> PLC –> IP3 and DAG –> Ca and PKC
What kind of receptor does histamine bind?
Gs
What kind of receptor does Ach bind?
Gq
What kind of receptor does dopamine bind?
Gi
What is the general structure of an RTK?
extracellular domain
alpha-helical transmembrane domain
intracellular TK domain
How does RTK signaling generalling work?
ligand binds to extracellular domain –> dimerization –> tyrosines Piate –> recognize adaptor proteins –> RAS-dependent and RAS-independent paths
both Piate spec proteins
What is the basic structure of insulin?
A chain = 21 aa
B chain = 30 aa
connected by 2 disulfide bridges
1 disulfide bridge within A chain
What is the difference btw inactive and active insulin?
inactive = stored in body as a hexamer
active = monomer
How is insulin synthesized?
preproinsulin mRNA –> preproinsulin protein –> goes to ER –> cleaved to proinsulin –> folded and moved to golgi –> packaged and cleaved in golgi –> mature granules = hexameric crystals (3 dimers)
What are the 2 pools of insulin corresponding phases of insulin release?
readily releasable pool = limited, 5%
reserve pool = 95%, granules must undergo mobilization
What does the RAS-dependent signaling of insulin do?
insulin binds RTK –> GRB-2 and IRS-1 –> RAS –> Piated proteins –> alterations in gene transcription (increased scrip of glucokinase –> glucose uptake, glucogen synthesis
What does the RAS-independent insulin signaling do?
insulin binds RTK –> Pi 3-kinase –> PKB –> Piated proteins –> alterations in protein and enzyme activity (more glut4, activation of glycogen synthase) –> glucose uptake, glycogen synthesis
How is insulin signaling terminated?
insulin-receptor complex is internalized in target cells by endocytosis –> either degraded or recycled
How does insulin affect its own receptor?
downregulates its receptor
decreases rate of synthesis/increases rate of degradation
How is insulin resistance quantified?
amount of glucose cleared from the blood in response to a fixed dose of insulin –> failure of expected response = resistance
What are the 3 main possibilities for insulin resistance currently being studied?
downregulation of insulin receptor
defects in insulin signaling (less GLUT4)
defects in insulin receptor (75 mutations ID’d)
What are the main defects in downstream insulin receptor signaling being studied?
defects in IRS1 and IRS2
Piation of serine instead of tyr in IR and IRS –> inhibits downstream signaling
Ser/Thr kinase activated by cytokines, FFAs, DAG, ceramide, etc –> impairs downstream signaling
Where are nuclear receptors
in nucleus
or in cytosol –> translocate to nucleus after ligand binds
What are the 3 major domains of nuclear receptors?
ligand binding domain (LBD)
activation function 1 domain (AF1) aka transcription activating domain
DNA binding domain (DBD)
What does AF1 on a nuclear receptor do?
independent of ligand binding
can modify conformation of entire receptor
What does DBD on a nuclear receptor do?
highly conserved
binds regulatory seq on DNA = hormone response elements (HREs) upstream of target gene
What are the primary and secondary responses to steroid hormones?
primary = proteins directly induced from steroid-receptor complex
secondary = primary protein shuts off its own genes –> turns on secondary response genes
What is ERalpha and where is it found?
estrogen receptor = transcription factor
expressed most abundantly in female repro tract
also in mammary gland, hypothalamus, endothelial cells, and vasc smooth muscle
What is ERbeta and where is it found?
estrogen receptor = transcription factor
expressed most in ovaries, prostate, w/ lower expression in lung, brain, bone, and vasculature
What is the mechanism of action of ER?
estrogen binds –> ER dimerizes –> promotes HAT activity –> activates transcription
How does tamoxifen work?
metabolized by liver to 4-hydroxy-tamoxifen –> inhibits ER –> promotes HDAC activity –> inhibits transcription
Where is ER located?
traditionally thought to be in the nucleus
some evidence that it is in the cytosol
estrogen binding –> dimerization and translocation to nucleus
What are the non-genomic ER signaling pathways?
some ERs located in the plasma membrane or caveolae in plasma membrane
GPCR and RTK type of receptors
metabolic changes
What hormones use a Gs receptor?
GCAPALT
glucagon
calcitonin
ACTH
PTH
ADH (V1 receptor)
LH and FSH
TSH
What hormones use a Gq receptor?
GAGOAT
GHRH
Angiotensin II
GHRH
Oxytocin
ADH (V2 receptor)
TRH
What hormones use an RTK to signal?
PIGI
prolactin
insulin
GH
IGF-1
