CELL BIOL (Perrino): Receptors Flashcards
What membrane proteins represent 50 percent of drug targets?
GPCR!!!
Can a ligand bind to more than one GPCR, and can the receptor bind to more than one ligand?
YEAH! they can both bind to a lot of GPCRs and ligands, respectively
How many transmembrane domains does EVERY GPCR have?
Seven! These domains are also the most conserved parts
What parts of GPCRs are diverse?
The binding site AND the cytosolic domain
Examples of ligands with a ton of receptors!
Adrenaline has 9. ACh has 5. serotonin has 15 GPCRs
What cells, tissues, and organ systems express GPCR and enzyme linked receptors?
ALL OF ‘EM
ALL alpha units of G protein serve to what?
serve as a GTPase to bind to GTP and then hydrolyze it
Once ligand binds to GPCR, what’s the first step?
the G protein complex (alpha, beta, gamma) docks to receptor protein. receptor protein!
What happens immediately after GDP-coupled alpha subunit binds to receptor?
GDP gets exchanged for GTP; and the BOTH alpha subunit and BY complex are considered activated
What does GTP cause the ABY complex in g proteins to do?
it activates AND dissociates them!
well, A apart from BY
Where do activated subunits go (usually the alpha)?
they find the TARGET protein on the cytosolic side of the membrane to attach to
What does the hydrolysis of GTP coupled alpha subunit do?
It causes the alpha to dissociate from target protein. and then alpha reassembles with BY. LAST STEP IN GPCR
describe cholera mechanism
binds to the α subunit so that it can no longer hydrolyze its bound GTP, causing it to remain in an active state that stimulates adenylyl cyclase indefinitely.
In alpha-andrenergic receptor what does activated g protein alpha subunit do?
It inhibits adenylyl cyclase! no cAMP
In alpha-andregenic receptor what does the activated BY complex do?
It activates the K+ channel for efflux of potassium
In alpha-andregenic receptor, what does the hydrolysis of the GTP coupled alpha subunit do?
like always, it causes ABY to reassociate!
What does pertussin toxin block?
the affects the GDP-ABY complex such that the subunits do not get activated because they remain bound. remember that it’s a Gi alpha for a target protein. So if it did work, the BY would probably be putting in work, just like the other alpha andregenic receptor examples.
What does PKA mean?
Protein KinASE
What does inactive PKA look like?
It has a dimeric regulatory subunit connected to an inactive catalytic dimeric subunit
What does cAMP do to the inactive PKA?
It binds to the REGULATORY subunit to make a cAMP-regulatory subunit complex. Additionally, this causes the release of the catalytic subunits (both separate) and now they become ACTIVE!
PKA activates what and blocks what in fight or flight?
active PKA inactivates glycogen synthesis and upregulates glycolysis production
Why does ligand for somatostatin up regulation produce a longer PKA response than, say, flight or fight?
Ligand activates PKA like usualy, but the activated PKA phosphorylates CREB,which is a DNA bnidning protein that somatostatin hormone gene transcription
is the cAMP/PKA cascade common in hormones?
Yup!
How can you deactivate cAMP pathway?
- PDE
2. phosphotase
What does PDE stand for and what does it do?
Phosphodiesterase breaks phosphodiester bonds and converts cAMP to regular inactive AMP
What does phosphotase do?
It removes phosphate groups from proteins, such as the CREB binding protein in the somastatin pathway
How specific are regulatory protein phosphotases?
They’re not specific at all. They’re very promiscuous
Main FX of phosphotases?
To dephosphorylate phosphate kinase dependent proteins
First step in PKC cascade after ABY activation
phosphoLIPASE C gets actiated and then breaks up DAG-IP3
Where does the free IP3 go?
it binds to a transporter on the lumen of the ER which causes a conformational change and therefore the release of CA++!!
What does the release of Ca++ in the PKC cascade do?
the Ca++ binds to the PKA C (DAG also binds to the PKA C), and then it activates it.
What does an acttvated PKA C do?
it phosphorylates a bunch of other proteins!
is calcium way higher in the cell or outside the cell?
Outside has [CA++] concentration by ten thousand fold
Why is Ca++ so low in the cytosol? (3 reason)
- active transport to ER
- active transport to MT
- calcium binding molecules in cytosol
What are the 2 ways to raise Ca++ in the cell?
- voltage gated calcium channels in nerve cells!
2. GPCR response that releases IP3 to bind to transporter on ER and allow CA++ to flow into cytosol
In cardiac myocytes, instead of IP3 what activates calcium efflux outside of ER?
Addition of calcium coming from the plasma membrane
Main mechanims for GPCR response? Occurs about 90 percent of time
the cAMP pathway that activates a PKA for fruther singaling
Now, how common is the PKA C pathway?
pretty common but not nearly as common as the cAMP pathway
In olfaction, what is the name of the target protein that activated Galpha
Adenylyl cyclase
What does adenylyl cylcase do in olfaction?
it actiates cAMP cascade
What does cAMP do in olfaction?
It binds to the Na+ transporter to allow sodium in and depolarize the cell. then signal goes to brain
Describe the signalling pathway of rod cells in dark.
rhodopsin inactivated; Gt (transducin) inactivated; low PDE; cGMP is active ; cell is depolarized; and then high rate of synapse
Describe signalling pathway of rod cells in light
Light activates rhodopsin and then G protein transducin is activated; this then activates phosphodiesterase PDE which then lowers the amount of cGMP (by breaking phosphodiesterbonds); and then therefore sodium channels close so the cell is hyperpolarized. low synapse rate
What happens if a GCPR has been on far too long”
It gets desensitized
What’s the first step in the GPCR phophorylation process?
Activated GPCR stimulates GRK, GRRRRRRKK, to phophorylate the GPCR at MULTIPLE sites. so then
What happens to the GPCR domain site after it’s multiphosphorylated?
ARRESTIN bdinds onto the domain part of the GPCR, completely blocking the cytosolic domain
How many domains do ALL tyrosine kinase receptors have?
JUST ONE!!!!!!!!!!!!! Unlike 7 in GPCR
_____ are usually growth factors
receptor tyrosine kinases
After receptor binds to RTK, what happens? And then what happens after that?
RTKs dimerize, and then they autophosphorylate each other
Tyr phophoyrylation WITHIN kinase somain increases or decreases kinase activity?
What about Tyr phosphorylation outside the domain?
INCREASES kinase activty?
provides docking sites for binding of other signaling proteins
