Further Dug Targets

Question 1

What are GPCRs

Answer 1

They are receptors that sit in the cell mem, waiting for signals from the outside world and they interact with G proteins - cross the membrane several times aka they have seven transmembrane helices

Question 2

What do GPCRS do?

Answer 2

• Several hundred devoted to smell
• Heart rate, speed and force of heart
• Relaxation of smooth muscle in lungs
• Eyes detecting light, light detected by gpcrs

Question 3

What is sumatriptan

Answer 3

It’s the commercial name for imigran and is used in the treatment of migraine

Question 4

What is cetirizine

Answer 4

Commercial name for zirtek and is used as a antihistamine

Question 5

What does it mean when a G protein is described as heterotrimeric

Answer 5

This means that it is composed of 3 subunits.

α, β, γ

Question 6

To which subunit does GDP bind to ?

Answer 6

α subunit

Question 7

Describe the events leading up to GPCR activation

Answer 7

1) An agonist molecule binds to the receptor causing a conformational change
2) G protein itself also undergoes a conformational change where a exchange happens in the α subunit. The affinity for GDP is lowered whereas the affinity for GTP is increased - exchange of GDP to GTP- activating the G protein

Question 8

What structure helps the Gprotein to attach to the cell membrane

Answer 8

Lipid molecules on the surface of the G protein adhere/embedd themselves into the membrane

Question 9

What happens after the activation of the Gprotein

Answer 9

The gpG protein undergoes dissociation- dissociation from the receptor and Gα from the heterotrimeric structure, β,γ stay together. Gα then goes on to activate the “effector”. Once at the effector molecule Gα, there is some catalytic activity- cleavage of the GTP molecule to GDP and Pi- now the α subunit no longer wants interact with the effector molecule

Question 10

At what point during the Gprotein cycle is the agonist released

Answer 10

Once the GTP molecule is hydrolysed back to GDP and Pi, the agonist molecule dissociates

Question 11

Do GPCPR coupling target only ion channels

Answer 11

No enzymes aswell

Question 12

What are the effector molecules of Gas?

Answer 12

The cAMP producing enzyme- adenylcyclase (converts ATP to CAMP)

Question 13

What is the function of cAMP

Answer 13

It activates the protein kinase A which regulates the activity of a large number of enzymes

Question 14

What does protein kinase A do

Answer 14

It increases the permeability of the cell membrane to Ca 2+ ions- Ca2+ channels open

Question 15

To what receptor is the Gas subunit bound to

Answer 15

β-adrenoreceptor

Question 16

What is the effector of the Gai/o protein?

Answer 16

Just like the Gas protein the effector molecule is the cAMP producing enzyme adrenylcyclase as well as potassium and calcium ion channels

Question 17

What is the receptor that Gai/o binds to?

Answer 17

Opioid M2 muscarinic receptor- activated by Ach

Question 18

What is the effect on the pottasium and calcium ion channels when activated by Gai/o?

Answer 18

The potassium channels allow a flux of K+ ions into the cells, aka the ion permeability increases whereas the permeability to Ca2+ decreases

Question 19

What receptor does Gaq bind to?

Answer 19

M1 muscarinic receptor or α1 adrenergic receptor

Question 20

What is the effector molecule of the Gαq protein?

Answer 20

Phospholipase C (PLC) which catalysts the breakdown of PIP2 into DAG and IP3

Question 21

What is the effect of increased levels of DAG

Answer 21

DAG activates protein kinase C which causes the phosphorylation of target proteins

Question 22

What is the effect of increased levels of IP3?

Answer 22

This causes the release ofCa2+ from intracellular stores

Question 23

What does Vibrio cholerae toxin do to cells?

Answer 23

Producing cholerae toxin that can cross the cell membrane interferes with the cell signaling pathway, it causes over activation of the cell signaling pathway that controls the activity of chloride channel proteins.
I.e. adds the ADP ribose molecule to your G protein and switch them permanently on and this injected by polluted water, crossing the epithelial mem of the gut and activate ion channels that secrete cl ions and water into the gut —> diarrhea, which could potentially cause blood clots due to the decrease in water in the blood

Question 24

Where GPCRs play a role

Answer 24

Eg for asthma where allergy and hyper reactivity causes constriction of the airway smooth muscle, you relax that with adrenaline or you can use an artificial adrenaline like substance to produce the same response but adrenaline cause increase heart rate if in flight or fight response thus fortunately asthmatics take salbutamol because it’s more selective for the adrenal receptors you find in the lungs

Question 25

What are receptor tyrosine kinases?

Answer 25

They are proteins that sit in the cell membrane that agonist molecules can bind to, activate and trigger a response in the cell, they are involved in mediating cell to cell communication and controlling a wide range of complex biological functions.- usually phosphoryle molecules

Question 26

What is the general structure of receptor tyrosine kinases?

Answer 26

``` They are usually composed of 3 domains A)Extracellular ligand-binding domain B)Transmembrane region C)intracellular kinase domain- puts phosphates on things In order of arrangement ```

Question 27

What is the general structure of receptor tyrosine kinases?

Answer 27

A) Extracellular ligand-binding domain B) transmembrane region C) intracellular kinase region- good at putting phosphates on things (In order of arrangement)

Question 28

What are 2 examples of RTKs?

Answer 28

Epidermal growth factor | Insulin

Question 29

What is the first thing that occurs with RTKs?

Answer 29

First thing RTKs do is form dimers if they already have not eg insulin receptor- One way in which this happens, is the agonist is simply able to bind to two receptors at once, this usually happens at the Extracellular ligand-binding domain Another way is that the agonist molecule changes the conformation of the receptor in such a way that it favors the receptor forming dimers

Question 30

What happens after a dimmer is formed between RTKs?

Answer 30

The active conformation is formed-and this dramatically changes the activity of the RTKs: A) the intracellular kinases region undergoes autophosphorylation (very active) this forms binding sites for other proteins which have domains that can interact with these phosphorylated regions B)once bound this activates the particular proteins that then go on to activate further proteins- causing a cascade of signaling pathways Notes some of these RTKs end up activating PLC—breakdown PIP2–IP3 increased—Ca2+ increases or DAG increases

Question 31

What happens with people who are diabetic/that have diabetes melitus

Answer 31

In diabetes people can extract the energy from food and sugars but they have a reduced ability to store this energy and by osmosis the sugars take out water with them and thus explaining the need to urinate. ‘Sweetened urine’

Question 32

What is the problem with diabetics

Answer 32

Without the necessary supply of enery the body starts to breakdown fats leading to ketoacidosis- when the blood become more acidic than body tissues. And this can be fatal

Question 33

What are some features of type 1 diabetes (4)

Answer 33

A) usually begins in childhood B)caused by severe underproduction of insulin C) often associated with the destruction of β cells in the pancreas D) also called insulin-defendant diabetes mellitus

Question 34

What are some feature of diabetes type 2

Answer 34

A) has a late onset- maturity onset diabetes B)impaired insulin response and secretion C)weight loss and diet control could be effective treatments D) also called non-insulin-dependent diabetes mellitus

Question 35

What does the does-response relationship depend on? (E)

Answer 35

A) Drug catabolism B) the relationship between drug binding and response-receptor activity C) the concentration-dependence of the drug binding to its site of action ( relationship between the conc. Of the drug and the amount that’s bound to the receptor)

Question 36

What is the law of mass action? - realtionship between drug concentration and occupancy

Answer 36

The rate of reaction is proportional to the once concentration of its reactants

Question 37

Law of mass action as an equation

Answer 37

A + R = AR Where the rate of forming the AR complex is proportional to the concentration of the A and R independently = (k + 1)[A][R]

Question 38

In the A + R —> AR equation, we know that the rate of forming the AR complex is proportional to the concentrations of A and R respectively, how else can we represent this relation ship?

Answer 38

A + R -(k + 1)—> AR

Question 39

What is the relationship between the rate of breakdown of AR and the concentration of AR?

Answer 39

The rate of breakdown ( defined as k-1x [AR]) is proportional to the concentration of AR NOTEbackward rxn defined as k-1

Question 40

What is (k+1)

Answer 40

It is the association rate constant

Question 41

What are the units of the association rate constant

Answer 41

M-1 s-1

Question 42

What is (k - 1)

Answer 42

It’s the dissociation rate constant

Question 43

What are the units of the dissociation rate constant

Answer 43

s-1

Question 44

What do we assume stands at equilibrium

Answer 44

That the rate of forming a complex = the rate of breakdown of AR (K+1J[A][R]=(k-1)[AR]

Question 45

What is the equation relating receptor population

Answer 45

RT= [R]+[AR]

Question 46

What is the equation relating the proportion of receptors

Answer 46

1=PAR + PR

Question 47

What does Ka represent

Answer 47

It’s the dissociation equilibrium constant | Ka = k-1/k+1 units= M

Question 48

What is the equation relating the proportions of receptors that are free and in a complex and Ka?

Answer 48

PR= Ka/ [A] x PAR Thus…. 1 = Ka/ [A] x PAR + PAR

Question 49

What is the Hill-Langmuir equation aka what is the equation that represent the relationship between drug concentration and receptor occupancy?

Answer 49

1= PAR ( 1 + Ka/[A] )

Question 50

What are the x and y-axis values when plotting to show the drug concentration and receptor occupancy (Hill-Langmuir equation)?

Answer 50

X-axis: log scale of agonist concentration in (nM) | Y-axis: PAR

Question 51

What do we have to assume to plot a straight line to represent the hill-Langmuir relationship?

Answer 51

A) y/ymax= PAR= Conc.A / conc.A + Ka After rearranging y/ymax = conc.A / conc.A + Ka B) y/ymax - 6y = conc A / Ka Then take log of both sides

Question 52

What’s an equation that describes the linear relationship of the hill Langmuir equation rather than explaining it

Answer 52

In notes