Lecture 2

1.
What to receptor tyrosine kinases do?
Mediate the actions of cytokines
2.
What are the parts of TKRs? (2)
"Extracellular ligand receptor, intracellular kinase"
3.
What are kinases?
Enzymes that phosphorylate other molecules
4.
Why are RTKs called RTKs?
They phosphorylate (kinase) intracellular tyrosine
5.
What does phosphorylation do?
"Turns an enzyme on or off, translocation of protein, alters action of protein"
6.
What are the domains of a TKR?
"Extracellular domain, transmembrane domain, juxtomembrane domain, kinase domain, C Terminal tail"
7.
What binding sites does phosphorylation create?
"Adapter protein, kinase, phosphatase, lipase"
8.
What receptors are essential for angiogenesis?
VEGFRs
9.
What pathological conditions are VEGFR dysfunction associated with?
"Cancer, RA, CVD"
10.
What type of receptor is VEGFR-2?
Ligand activated TKR
11.
What cell actions is VEGFR-2 associated with?
"Cell survival, no production, cell migration, proliferation, PGI2 production"
12.
What happens when a ligand binds VEGFR-2?
Autophosphorylation of intracellular domain -> activation of PLC -> hydrolysation of PIP2 into DAG and IP3 -> DAG activates PKC -> Raf -> MEK -> ERK -> gene transcription to increase cell proliferation
13.
How are angiogenesis inhibitors used therapeutically?
Inhibition of cancer growths
14.
How are angiogenesis stimulators used therapeutically?
To promote blood flow (eg. in ischaemic tissue)
15.
Where are steroid/nuclear hormone receptors located?
Intracellulary
16.
What is the process of steroid receptor activation?
Hormone enters cell (diffusion) -> forms dimer with receptor -> dimer translocates into nucleus -> binds to gene sequence target site -> transcription of genes
17.
What are examples of LGICs?
"Nicotinic, GABA receptors"
18.
What are examples of GPCRs?
"Dopamine, muscarinic, adenosine receptors"
19.
What are examples of TKRs?
"Insulin, GF, cytokine receptors"
20.
What are examples of NRs?
"Steroid, thyroid"
21.
What is the structure of LGICs?
Oligomeric
22.
What is the structure of GPCRs?
Monomeric
23.
What is the structure of TKRs?
Transmembrane helix with extracellular and intracellular domains
24.
What is the structure of NRs?
Monomeric
25.
What forces bind drugs to receptors?
"Van der Waals, H-bonds, ionic bonds, covalent bonds"
26.
Which type of bond is irreversible?
Covalent
27.
What is the equation for fractional occupancy (FO)?
FO equals [Ligand] / (Kd + [Ligand])
28.
What is Kd?
Affinity constant. [Drug] when FO is 50% saturation
29.
How does concentration relate to level of affinity?
Lower [drug] at 50% FO is higher affinity
30.
Why is a biological response not a good measure of affinity?
The FO and biological response are not proportional (may only require small FO to elicit max response)
31.
What is a better relationship than affinity to measure drug efficacy? 
[Drug] vs % effect (concentration/response curve)
32.
What does EC50 measure?
Potency of drug agonist whenb [drug] is 50% EMax (100% effect)
33.
What concentration of drug EC50 shows high potency?
Lower EC50 > lower concentration required to elicit max response > higher potency
34.
What is efficacy?
The measure of a drug's ability to bind to a receptor and cause change in receptors action (EMax)
35.
What is an agonist?
A drug with positive efficacy (activation)
36.
What is an inverse agonist?
A drug with negative efficacy (inactivation)
37.
What is an antagonist?
A drug with no efficacy (block)
38.
What type of agonist cannot produce max response at saturation?
Partial agonist
39.
What is max response of a tissue determined by?
"Efficacy, tissue properties"
40.
 are the classes of antagonists?
"Irreversible antagonist, reversible competitive antagonist"
41.
What effect does a reversible competitive antagonist have on an agonist response curve?
Rightward shift
42.
What ultimate effect does an irreversible antagonist have on agonist response curve?
Flattens it
43.
With low [irreversible antagonist] the agonist response curve shifts to the right as with reversible competitive antagonists. Why?
Low FO needed to achieve Emax
44.
What is the result of receptor equilibrium when an agonist is introduced?
Equilibrium shifts to activated receptor state
45.
What is the result of receptor equilibrium when an antagonist is introduced?
No shift in equilibrium
46.
What is the result of receptor equilibrium when an inverse agonist is introduced?
Equilibrium shifts to resting receptor state
47.