Further Dug Targets Flashcards
What are GPCRs
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
What do GPCRS do?
- 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
What is sumatriptan
It’s the commercial name for imigran and is used in the treatment of migraine
What is cetirizine
Commercial name for zirtek and is used as a antihistamine
What does it mean when a G protein is described as heterotrimeric
This means that it is composed of 3 subunits.
α, β, γ
To which subunit does GDP bind to ?
α subunit
Describe the events leading up to GPCR activation
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
What structure helps the Gprotein to attach to the cell membrane
Lipid molecules on the surface of the G protein adhere/embedd themselves into the membrane
What happens after the activation of the Gprotein
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
At what point during the Gprotein cycle is the agonist released
Once the GTP molecule is hydrolysed back to GDP and Pi, the agonist molecule dissociates
Do GPCPR coupling target only ion channels
No enzymes aswell
What are the effector molecules of Gas?
The cAMP producing enzyme- adenylcyclase (converts ATP to CAMP)
What is the function of cAMP
It activates the protein kinase A which regulates the activity of a large number of enzymes
What does protein kinase A do
It increases the permeability of the cell membrane to Ca 2+ ions- Ca2+ channels open
To what receptor is the Gas subunit bound to
β-adrenoreceptor
What is the effector of the Gai/o protein?
Just like the Gas protein the effector molecule is the cAMP producing enzyme adrenylcyclase as well as potassium and calcium ion channels
What is the receptor that Gai/o binds to?
Opioid M2 muscarinic receptor- activated by Ach
What is the effect on the pottasium and calcium ion channels when activated by Gai/o?
The potassium channels allow a flux of K+ ions into the cells, aka the ion permeability increases whereas the permeability to Ca2+ decreases
What receptor does Gaq bind to?
M1 muscarinic receptor or α1 adrenergic receptor
What is the effector molecule of the Gαq protein?
Phospholipase C (PLC) which catalysts the breakdown of PIP2 into DAG and IP3
What is the effect of increased levels of DAG
DAG activates protein kinase C which causes the phosphorylation of target proteins
What is the effect of increased levels of IP3?
This causes the release ofCa2+ from intracellular stores
What does Vibrio cholerae toxin do to cells?
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
Where GPCRs play a role
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
What are receptor tyrosine kinases?
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
What is the general structure of receptor tyrosine kinases?
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
What is the general structure of receptor tyrosine kinases?
A) Extracellular ligand-binding domain
B) transmembrane region
C) intracellular kinase region- good at putting phosphates on things
(In order of arrangement)
What are 2 examples of RTKs?
Epidermal growth factor
Insulin
What is the first thing that occurs with RTKs?
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
What happens after a dimmer is formed between RTKs?
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
What happens with people who are diabetic/that have diabetes melitus
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’
What is the problem with diabetics
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
What are some features of type 1 diabetes (4)
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
What are some feature of diabetes type 2
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
What does the does-response relationship depend on? (E)
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)
What is the law of mass action? - realtionship between drug concentration and occupancy
The rate of reaction is proportional to the once concentration of its reactants
Law of mass action as an equation
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]
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?
A + R -(k + 1)—> AR
What is the relationship between the rate of breakdown of AR and the concentration of AR?
The rate of breakdown ( defined as k-1x [AR]) is proportional to the concentration of AR
NOTEbackward rxn defined as k-1
What is (k+1)
It is the association rate constant
What are the units of the association rate constant
M-1 s-1
What is (k - 1)
It’s the dissociation rate constant
What are the units of the dissociation rate constant
s-1
What do we assume stands at equilibrium
That the rate of forming a complex = the rate of breakdown of AR
(K+1J[A][R]=(k-1)[AR]
What is the equation relating receptor population
RT= [R]+[AR]
What is the equation relating the proportion of receptors
1=PAR + PR
What does Ka represent
It’s the dissociation equilibrium constant
Ka = k-1/k+1 units= M
What is the equation relating the proportions of receptors that are free and in a complex and Ka?
PR= Ka/ [A] x PAR
Thus….
1 = Ka/ [A] x PAR + PAR
What is the Hill-Langmuir equation aka what is the equation that represent the relationship between drug concentration and receptor occupancy?
1= PAR ( 1 + Ka/[A] )
What are the x and y-axis values when plotting to show the drug concentration and receptor occupancy (Hill-Langmuir equation)?
X-axis: log scale of agonist concentration in (nM)
Y-axis: PAR
What do we have to assume to plot a straight line to represent the hill-Langmuir relationship?
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
What’s an equation that describes the linear relationship of the hill Langmuir equation rather than explaining it
In notes
