Cell signaling II (Sept. 11 -Simmons) Flashcards
What is PIP(4,5)P2
Phophoinositol bis-phospate. Synthesized from PI, with additional phosphates on 4,5 -OH residues of inositol sugar
How is PIP2 (shorthand) attached to the plasma membrane
Attached to the inner leaflet. There are 2 fatty acids embedded in the PM that are attached to the inositol sugar at 1’-OH via a glycerol molecule
We learned the Gs and Gi pathways were associated with cAMP. What type of pathways is associated with PIP2 and what is the target enzyme is associated with the GPCR
Gq pathway.
Phospholipase C-beta
Phospholipase activates these 2 pathways by cleaving PIP2
- Diacylglycerol -associated with PM ->activates Protein Kinase C
- Inositol tri-phosphate (IP3) -> free floating which releases Ca2+ from ER
How is Ca2+ conc. maintained so low in cytosol?
There are Na+ driven anti porters in PM as well as ca2+ active energy pumps to move calcium out of cell.
In addition, There are Ca2+ binding proteins in cell, pumps that move calcium into ER, and pumps into mitochondria (using an H+ gradient)
True or false - higher levels of a drug which activates Gq pathway cause higher levels of Ca2+ oscillation in cells
False. Frequency of the spike oscillation increases - not the amplitude
Ca2+ movement is described as waves. This is due to the spread of _____ moving across an area inducing ______ nearby
- Calcium
2. channels
Describe the structure of calmodulin
- Shaped like a dumbbell (globular portion at each end connected by flexible helix)
- Can bind up to 4 Ca2+ ions (2 each head)
What is the function of calmodulin?
If at least 2 Ca2+ bind -> cause the calmodulin to bind to target proteins and affects their activity
Describe the mechanism of calmodulin binding to CaM kinase II
Calmodulin binds calcium and acrobats it to allow it to bind to inactive target kinase at the inhibitory domain. Autophosphorylation occurs to fully activate the kinase. Remains active even when calcium levels have dropped and calmodulin has dissociated (as long as activation phosphate remains bound)
True or False. All PKCs require diacylglycerol and Ca2+ for activation.
False. Out of 11 PKC, 4 of them explicitly require Ca2+ to become fully active
How are Ca2+ oscillations recognized by a cell?
Sufficient number of Ca2+ oscillations increase the activity of the CAM kinase to a maximum level of activity. The body can recognize these levels of activations…becomes accustomed and allows lower level of calcium to maintain a high level of activity of CAM kinases.
List the function of these 3 molecules and the mechanism of what they affect briefly (the kinase)
- cAMP
- cGMP
- Ca2+
- Protein Kinase A
- Protein Kinase G
- Protein Kinase C, CaM Kinase-II, myosin light chain kinase, phosphorylase kinase
How many families of adrenergic receptors are there? And what pathway does each affect.
9 families, a1a, a2b, b1, b2, etc.
Gq - a1 family
Gi/Go - a2 family
Gs - beta family
Notable exceptions: Beta 3 activates all 3 pathways
What are the Gs, Gi, Go, and Gq pathways usually responsible for
Gs - stim. cAMP -> vasodilation, lipolysis, increased heart rate
Gi - inhib. cAMP -> vasoconstriction, increased epinephrine > norepinephrine
G0 - k+ and phospholipase C -> same effects as Gi?
Gq - phospholipase C -> vasoconstriction, cardiac growth
Know the general features of agonist, antagonist, and endogenous molecules
Agonist - only affects one family of receptor
Antagonist - selective blocks the binding of endogenous molecules from activating a particular family of receptors
How does NO work to cause vasodilation?
No -> activates guanylyl cyclades -> increases cGMP -> increases PKG activity -> relaxation
How is calmodulin involved in NO production?
Activated calmodulin is involved creation of NO from L-arginine and L-citrulline…using NADPH as a reduction molecule.
ACTIVATION of NOS (nitrous oxide synthetase)
Bradykinin acts to cause vasodilation. Describe the binding of this molecule and the signal transduction.
- Bradykinin binds to GPCR (Gq)
- Phospholipase C activated and cleaves to form IP3 and DAG
- Increase in Ca2+
- Calmodulin activates and causes activation of NOS
- NO gas is soluble and moves into smooth muscle cells
- Binds to Guanylyl cyclases
- Increase in cGMP created from GTP
- Increase in PKG
How is the previous pathway altered when using pharmacological agents: nitrovsodilators?
Bypass endothelial pathway. Direct affect on NO and NOS production.
