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27 Cards in this Set

  • Front
  • Back
7TM receptors consist of...
7TM receptor (always specific), heterotrimeric G protein (alpha unit with GDP/GTP, beta and gamma units)
upon binding of epinephrine to epinephrine receptor, what happens?
Galpha subunit trades GDP for GTP and dissociates from receptor, beta and gamma subunits dissociate, Galpha binds to adenylate cyclase, which turns ATP into cAMP
cyclic AMP
second messenger
activates protein kinase A
opens up its catalytic sites that are normally blocked by pseudosubstrate
what kind of amino acids does protein kinase A phosphorylate?
serine and threonine
epinephrine promotes...
-phosphorylation and activation of glycogen phosphorylase
-phosphorylation and inactivation of glycogen synthase
-phosphorylation and activation of triacylglycerol lipase (induces lipolysis--breakdown of triacylglycerides)
how are 7TM receptors inactivated?
1) Galpha subunits have intrinsic GTPase activity, so hydrolyze GTP to GDP and GDP-Galpha re-associates with rest of trimer
2) dissociation of ligand from receptor
3) kinases phosphorylate unoccupied carboxyl tail of receptor/hormone complex, this allows beta-arrestin to bind which blocks any more Galpha proteins from being activated
7TMRs and phosphoinositide cascade
1) G-proteins activate phospholipase C
2) phospholipase C cleaves PIP2 into IP3 (soluble and diffiusible) and DAG (membrane associated)
3) IP3 releases Ca2+ from intracellular stores
4) DAG and Ca2+ activate protein kinase C
2 reasons Ca2+ make a good second messenger
1) present at very low levels in cells, so can changes are easily detected
2) binds with high affinity to proteins to induce conformational changes
calmodulin
activated by Ca2+
has 4 Ca2+ binding sites
member of EF-hand protein family (helix-loop-helix)
diffusible allosteric effector
2 examples of calmodulin use
CaM-kinase: when calcium binds to calmodulin, they bind to CaM kinase to activate it
phosphorylase kinase: calmodulin is integrated into subunit, requires Ca2+ and phosphorylation to be completely active (this phosphorylates and activates glycogen phosphorylase)
Cholera
toxin turns Galphas to a permanent ON state, so continuous activation of adenylate cyclase and PKA; intestinal PKA regulates activity of Cl- channels and Na/K exchanger; deregulation of ion transport resulting in massive loss of NaCl and water
Whooping Cough
Galphai normally inhibits adenylyl cyclase
this toxin traps G-protein in OFF state (can't exchange bound GDP for GTP)
adenylate cyclase is now DIS-inhibited (made active) leading to increased levels of cAMP, altered regulation of Ca2+ and K+ channels
the Insulin Receptor structure
receptor tyrosine kinase
dimer, each subunit consisting of alpha and beta subunit
alpha and beta linked by a disulfid bond
2 alpha subunits form insulin binding site, beta subunit includes protein kinase domain
what happens upon insulin binding?
-forces beta subunits together, which phosphorylate tyrosine residues in activation loops
-these phosphorylated sites serve as docking sites of insulin-receptor substrates (IRS)
-docking of PI3K to IRS proteins localizes enzyme to membrane where it can phosphorylate PIP2 to PIP3
-PIP3 activates PDK1 which phosphorylates (activates) Akt (protein kinase B; not membrane bound)
effects of insulin on glycogen synthesis
insulin activates PI3K/Akt signaling
protein kinases phosphorylate and INACTIVATE glycogen synthase kinase so glycogen synthase remains active
inactivation of insulin receptor by phosphatases
protein tyrosine phosphatases dephosphorylate receptor
protein ser/thr phosphatases desphosphorylate Akt, etc.
PTEN dephosphorylates PIP3
EGF receptor structure
exist as monomers--each unit binds one molecule of EGF
EGF binding causes dimerization
kinase is always active, but can only interact with its substrate after dimerization
Ras
small G-protein activated by EGF binding to receptor
when it trades GDP for GTP, becomes activated
can bind to and activate protein kinases
promiscuous--activates many different things
EGF receptor signal termination
Ras has intrinsic GTPase activity
GTPase-activating proteins facilitate GTP hydrolysis
Ras and cancer
Ras is frequently mutated in cancer
mutations can lead to an inability to hydrolyze GTP so leave Ras in permanent ON state
Rous sarcoma virus
-normal signaling of receptor tyrosine kinase is terminated by tyr phosphorylation
-protein introduced by virus lacks tyrosine, so is always active
-leads to unregulated growth
if EGFR is overexpressed in cancer (usually epithelial cancers), what can be done to treat it?
Cetuximab competes with EGF for binding site on receptor and blocks ligand-receptor interactions (monoclonal antibody)
if Her2 receptor is overexpressed in breast cancer, what does overexpression promote and what can be done to treat it?
promotes signaling in absence of EGF
Trastuzumab inhibits Her 2 activity (monoclonal antibody)
for steroid hormones, ligand binding does what?
induces a shift in conformation
conformational change at helix 12 creates binding site for coactivator
coactivators facilitate changes in gene expression by modifying chromatin structure and recruiting RNA polymerase
adenylate cyclase
changes ATP into cAMP upon activation by g proteins
protein kinase a
phosphorylates at ser and thr residues
activated by cAMP
4 examples of second messengers
IP3, DAG, Ca ions, cAMP