9-11 Cell Signaling II Flashcards
How does activated phospholipase-CB come about?
2)What does enzyme this make?
1-[Gq]coupled receptor after signaling molecule activates it, it then activates its alpha subunit which stimulates target phospholipase-CB
2)PCB cleaves minor membrane lipid [PI45P2] to make diacylglycerol and inositol 1,4,5triphosphate(IP3)!
Where is the [PI45P2] located?
2)What is the importance of this thing?
1) It’s fatty acid tails are embedded in the inner lipid monolayer of the Plasma Membrane
2) [PI45P2] is cleaved by activated phospholipase-CB to make diacylglycerol and IP3
PIP Kinase
Kinase that performs the 2nd and last phosphorylation of PI4p to make [PI45P2]
1st one is done by regular PI Kinase
After [___] is cleaved to finally create diacylglycerol and IP3..what does each of these do?
[PI45P2] is cleaved by phospholipase-CB first to create these two!
A: diacylglycerol=activates Protein Kinase C(also a Ser/Thr required kinase)
B: IP3= INC cytosolic Ca+ by releasing it from ER
How does IP3 work in Ca+ release?
2)How does the Plasma membrane assist in this?
IP3 binds to specific ER Ca+ channels which allows for Ca+ to move DOWN its gradient into the cytosol
2)AFTER this occurs PM may also sometimes open its Ca+ channels to allow for Ca+ to rush inside, sustain cytosol levels or replenish ER levels
There are ___protein Kinase C forms. 9 of them are activated by ______ but 4 of PKC require ____ and ___
11 protein Kinase C forms
9 require only DAG for activation
4 require DAG AND Ca+ for activation!
___ion has to be kept VERY LOW in the cytosol so it can act as a good signaling component when released.
2)What are the 5 ways this ion is kept low in cytosol?
Ca+ is VERY LOW in cytosol so when released from ER it can act as good signaling component and will diffuse DWN its gradient
- Na+/Ca+exchanger pumps 3 Na+ into cell and 1 Ca+ out
- Ca+ pump dephosphorylates ATP to pump out Ca+
- ER membrane Ca+ pump pushes Ca+ inside ER
- Calcium-binding molecule in cytosol
- Active import into mitochondria w/H+ symport
Describe the Ca+ wave feedback Loop!
2) How is the loop/wave ultimately terminated??
3) What’s another name for this feedback loop?
IP3 inducing Small, localized INC in cytosolic Ca+(AKA puffs/sparks) at 1 point can stimulate the opening of OTHER Ca+ Channels nearby!—>waves of Ca+ release mvmnt across the cell!
2) Eventually feedback INHIBITION from lots of Ca+ closes channels and Ca+ is pumped BACK into ER or out of cell
3) [Calcium-induced calcium release]
[T or F] Cytosolic Ca+ actually changes and varies over time and space
TRUE!
How is the concentration of a signaling molecule related to Ca+ wave oscillations?
2)What is an example of this?
INC in signaling molecule concentration(which stimulates [Gq] protein) will INC transient Ca+ wave oscillation FREQUENCY
2)INC Vasopressin conc. in the liver cell INC FREQUENCY of Ca+ wave oscillations in the cytosol
Calmodulin is a super ______protein!
2)Explain how Calmodulin is related to Ca+
3)What does Calmodulin look like?
Calmodulin is a SUPER CONVERSED protein!(Can not change the structure/coding too much).
2) -Calmodulin has 4 Ca+ binding sites BUT ONLY TAKES 2 Ca+ to bind in order to activate
- activated calmodulin complex binds to other enzymes & membrane transport proteins for INC/DEC activity
3)”Boxing Gloves” dimer with an N-terminal and C-terminal end
CaM-kinases
2)What’s the very special CaM-kinase and why?
Activated by Calmodulin these [calmodulin-dependent protein kinases] can carry the Ca+ signal cascade on forward by phosphorylating proteins with serine/threonine AA and altering their activity
“they’re [Ca+-Calmodulins] lil helpers”
2)CaM-kinase II is special because it can autophosphorylate ITSELF (on adjacent subunit)! after being partially activated by Ca+-calmodulin binding
1) CaM-kinase II is a complex with ___subunits and has the unique ability of ____. How does it do this?
2) What happens when Ca+ DEC around CaM-kinase II?
3) Explain “memory trace”
4) How does this unique feature change the binding affinity of [Ca+-calmodulin]
1) CaM-Kinase II has 12 subunits and can autophosphorylate itself! [Ca+-calmodulin] binds to CaMII which partially activates it kinase and then CAMII phosphorylates its own adjacent subunit! = fully active
2) DEC in Ca+ signal–>calmodulin detaches–>BUT because of the autophosphorylation CAMII enzyme stays active until phosphatase removes tht phosphate :-O
3) a “memory trace” refers to the fact that the Ca+ signal still does it job EVEN W/OUT Ca+ PRESENT
4)Autophosphorylation INC binding affinity for
[Ca+-calmodulin] which delays its release. = even a small subsequent Ca+ signal can quickly reactive the enzyme fully!
GREATER FREQ. of Ca+ wave oscillations = _____[INC/DEC] activity of CaM-Kinase II in a cell.
2)Why is this?
3)What happens once CaM-Kinase II reaches this new state caused by GREATER FREQ. in Ca+ wave oscillations?
GRTR FREQ. of Ca+ wave oscillations=INC activity of CaM-Kinase II.
2) CaM-KinaseII interprets freq. of Ca+ oscillations and knows if there is too much time between Ca+ spikes phosphatase cleave its auto-phosphate off/deactivate it. **Less time between spikes allows all of the enzyme to not be completely inactive b4 new spike comes—>more and more of the enzyme will become activated over time
3) Once in it’s new “hyper” state cAMKII will only need low freq. of Ca+ signals due to the [Ca+-calmodulin] high affinity binding made from autophosphorylation
FYI: The effect a signaling molecule has on a cell doesn’t necessarily depend on the signaling molecule itself but the__________
Effect a signaling molecule has on a cell depends partly on which ***set of proteins are available for phosphorylation once the signaling molecule starts the process
How does Calmodulin stimulate smooth muscle contraction?
[Ca+-calmodulin] complex together activate Myosin light chain Kinase ——>which produces
Myosin light chain-P——->smooth muscle contraction
How does Calmodulin assist in producing Glucose?
[Ca+-calmodulin] complex together activate Phosphorylase Kinase—–>which produces
Glycogen phosphorylase-P—->MAKES GLUCOSE!
The adrenergic hormones Epinenphrine (_____) and NorEpi (____) are special because they have 9 different ________ and can act on ___ of different tissues with different resulting functions!
Epi(Adrenanline) and NorEpi(Noradrenaline) adrenergic molecules have 9 different G-protein coupled receptors which mean they can act on G-proteins in MULTIPLE tissues with MULTIPLE resulting functions
Name the G-protein coupled receptor subtypes AND the main G-protein that’s activated for the:
Type [a1] adrenergic receptor family
a1A = Gq activation a1B = Gq activation a1D = Gq activation
Name the G-protein coupled receptor subtypes AND the main G-protein that’s activated for the:
Type [a2] adrenergic receptor family
a2A= Gi/Go activation
a2B=Gi/Go activation
a2C= Gi/Go activation
(**Gi –>STOPS adenyly cyclase)
Name the G-protein coupled receptor subtypes AND the main G-protein that’s activated for the:
Type [Beta] adrenergic receptor family
B1 = Gs activation B2 = Gs activation B3 = Gs/Gi/Go activation "it's special"
Agonist
Drugs that ACTIVATE a specific adrenergic receptor
ANTagonist
BLOCKS epinephrines ability to bind to an adrenergic receptor by binding more competitively!–>Inactivates Receptor
Why is it some drugs can target the [a2A] adrenergic receptor w/out actually binding to its sister receptor [a2B]?
Different adrenergic receptor subtypes[a2A vs. a2C] have hormone bindings sites that are structurally different from one another –>allows hormones to target subtypes
Epinephrine hormone has the ability to bind to _____ adrenergic receptors
Epinephrine BINDS TO ALL 9 ADRENERGIC GCPR receptors!
Nitric Oxide (NO) is a ____ ____ produced by ______ from _____, ____ and ___ parts.
Nitric Oxide (NO) is a signaling molecule that is produced by Nitric Oxide synthase [NOS]–> using AA arginine, oxygen and NADPH parts.
eNOS or NOS3 (Nitric Oxide synthase/NOS) are responsible for making ____. How are these enzymes activated in the 1st place??
[eNOS or NOS3 ] make Nitric Oxide (NO)!
2) They’re activated when hormones(like bradykinin or ACTH) activate Gq protein
- –>which then stimulates [Ca+-calmodulin] to eventually turn on these NOS enzymes
After being produced by _____ in the ______….how does Nitric Oxide (NO) actually does its job of relaxing smooth muscles?
Nitric Oxide synthase(NOS)[eNOS/NOS3] produce NO IN THE ENDOTHELIUM.
1)NO passes thru membranes from endothelium(where it’s made) into the Smooth MUScle to activate/bind to heme group of [soluble guanylyl cyclase/SGC]—->
2) this will convert< GTP into cGMP > ——.–>
3) cGMP then activates Protein Kinase G(PKG)——————>
which phosphorylates select Ser/Thr Proteins in the smooth muscle cells = relaxation/dilation
During the synthesis of Nitric Oxide (NO) from ______, ______ and _____. What is the name of the final byproduct which isn’t used?
2)Where does NO synthesis/creating naturally occur?
During synthesis of Nitric Oxide (NO) from AA arginine, oxygen and NADPH the byproduct [L-Citrulline] is left over and not used!
2)NO is first made in the ENDOTHELIUM and then it passes into the smooth muscle
What are 2 natural molecules which can start up the NO synthesis process?
THESE can start up the NO synthesis process!
- Bradykinin Hormone
- Acetylcholine from nerves in vessel wall
Draw Out/Visualize the ENTIRE PROCESS of Vascular Relaxation Mediated with Nitric Oxide. [7] :-O
2)This process is _____-dependent
1: Bradykinin or ACTH stimulate coupled receptor to activate Gq-protien
2: Gq-protein activates Phospholipase C which makes DAG and IP3
3: IP3 goes off to cause ER Ca+ release which Ca+ then joins with Calmodulin–>[Ca+-Calmodulin] complex
4: [Ca+-Calmodulin] binds & turns on NOS enzymes which make NO from Arg, O2 and NADPH.
5: NO travels out of endothelium, passes membranes and into smooth muscle cells to activate/binds to heme of SGC
6: SGC converts and cGMP activates PKG
7: PKG phosphorylates select Ser/Thr proteins in smooth muscle cell—>VASODILATION/RELAXATION!
(This process IS ENDOTHELIUM dependent)
Describe the ____-INDEPENDENT process of Nitric Oxide Vasodilation/Relaxation in smooth muscle cell
DRUGS like bypass (NO)-endothelium synthesis and PUSHES (NO) DIRECTLY into smooth muscle cell for vasodilation/relaxation process
endothelium-INDEPENDENT VASODILATION
