Lecture 11 Information Flashcards
What determines interactions between the ligand and receptor?
weak interactions
What are components of sensitivity?
high affinity
cooperativity
amplification of signal
Cooperativity in ligand binding receptor
refers to large changes in receptor activation with small changes in ligand concentration (allostery)
Desensitization
cells need to be able to down regulate signal transduction pathways
Receptor activation triggers a feedback inhibition circuit that shuts off the receptor or removes it from the cell surface
Integration
the cell has to look at the sum of all the different messages it is receiving and determine a response
some receptors could be sending opposing signals
List the different types of signal transduction mechanisms (for our class)
1) G-protein coupled receptors
2) Receptor tyrosine kinases
3) Receptor guanylyl cyclase
4) Internal receptors
What are the 3 components of G-protein coupled response?
Plasma membrane receptor that binds the ligand
Intracellular g-protein
Effector enzyme that gets turned on as a result of this process
What is the receptor of the GPCR pathway made of?
7 transmembrane structures, mostly alpha helices, some beta-pleated sheets
G-protein subunits
alpha, beta, and gamma subunits
usually found in the inactive form and bound to GDP
when GDP converts to GTP, the alpha subunit detaches
Epinephrine mechanism
binds to specific receptor on the cell’s surface and triggers a conformational change in the g-protein
GDP gets converted to GTP and the alpha subunit detatches
the alpha subunit activates adenylyl cyclase which catalyzes the formation of cAMP
cAMP serves as a secondary messenger to activate protein kinase A
Protein Kinase A
allosterically activated by cAMP
starts a phosphorylation cascade of enzymes that catalyze the removal of glucose from glycogen
glucose can be used in the bloodstream for energy during flight or fight response
Different types of G-protein coupled receptors
stimulatory form (Gs) inhibitory form (Gi)
Inactive form of tyrosine kinase receptor
monomers
Active form of tyrosine kinase receptor
dimerized
activated through phosphorylation cascade
Autophosphorylation
tyrosine kinases ability to phosphorylate and activate the tyrosine residues on itself
Examples of tyrosine kinase receptors
insulin and epidermal growth factor (EGF)
Receptor guanylyl cyclases
have an extracellular component that is able to bind the ligand
have an intracellular component that works directly as an enzyme and cyclizes GMP (cGMP)
NO-activated version of guanylyl cyclase
doesn’t have attachment to a transmembrane protein
important for smooth muscle relaxation because it converts GTP to cGMP
Viagra
inhibits an enzyme, phosphodiesterase, that would degrade cGMP
leads to higher levels of cGMP and an erection
Nuclear receptors
proteins in the nucleus or cytoplasm that respond to steroid hormones, retinoic acid, and thyroid hormone
alter gene expression by directly binding to DNA
Thyroid hormone
needs to use a protein channel to cross the membrane in order to reach a nuclear receptor
cannot cross the membrane on its own
How fast do nuclear receptors work?
slowly
puberty takes years for steriod hormones to work
Estrogen
needs a carrier protein to transport since it can’t dissolve in the blood
binds a cytoplasmic receptor and then the receptor goes to the inside of the nucleus where it can directly interact with DNA
Phosphodiesterase
breaks down cAMP by converting it to AMP
desensitizes the epinephrine pathway
Cholera inhibits …
inhibits the ability of the g-protein’s alpha subunit to convert GTP to GDP
the pathway stays activated and get more and more cAMP
What happens when cAMP builds up with cholera?
stimulates an epitheal cell that lines the intestine to take chloride from inside the cell and put it in the lumen of the intestine
water follows Cl- and Na+ and will build up in the lumen of the intestine
too much water in stool and will become dehydrated quickly
Why does cholera want to excrete large amounts of water?
the toxin gets flushed out of the body and enters the water where it can infect more people
spreading itself to suitable hosts
Pertussis toxin
prevents GDP from converting to GTP
still leads to over production of cAMP (not sure)
Calmodulin
regulatory subunit of calcium dependent enzymes
When guanlyl cyclase make cGMP what type of bond to they make?
a phosphate ester
Acetylcholine
triggers the opening of a ligand-gated ion chanel
acetylcholine is positively charged
acetylcholine mainly produces conformational changes
Why do steriod hormones use carrier proteins?
they are too hydrophobic to dissolve in the blood by themselves
Steriod hormone response elements
are sequences in the DNA that when bound to the receptor-hormone complex trigger transcription
Transducin
a G-protein involved in visual signal transduction
Myosin
an example of a type of protein that can be phosphorylated by cyclin-dependent protein kinases
Amplification
small amounts of signal will trigger phosphorylation cascades that result in big intracellular changes
How does cholera activate the alpha-subunit of the g-protein?
ADP-ribosylation which is a type of covalent modification
What regulates protein kinase C?
DAG and Ca2+
What proteins are phosphorylated in response to insulin?
IRS-1
phosphatidyl inositol-4,5-bisphosphate
Do cyclins catalyze the phosphorylation of proteins?
no
Glycogen synthase kinase
inhibits glycogen synthase
SH2 domains bind sequences containing
phosphotyrosine
What does cAMP do in cholera pathway? (according to textbook)
regulates Na+ levels
What is a possible treatment for cholera?
replace fluids and electrolytes
Vassopressin
a peptide hormone
triggers vasoconstriction (opposite of Viagra causing increased blood flow and vasodialation)
vassopressin acts by elevating Ca2+ levels as a secondary messenger
Describe all the sources of amplification in the insulin receptor system
in order, insulin receptor, IRS-1, Raf, MEK, ERK;
ERK activates a transcription factor, which stimulates mRNA production.
Examples of secondary messengers
cAMP and Ca2+
cGMP
triggers vasodilatation, increasing blood flow and causing an erection
RNA polymerase
binds to the promoter with help from nuclear receptors
controls gene expression
