Lecture set 3

Question 1

intracellular receptors

Answer 1

unionized lipid soluble ligand like sex steroids and vitamin D
- They bind to specific DNA sequences and can lead to transcription of genes (receptors are slow)
Therapeutic significance
- these drugs take a while for their effects to be seen
- the effects can persist after the agonist concentration has been reduced to zero
Ex) mechanism of glucocorticoid action
- the steroid binds to the ligand binding domain (orthosteric site)
- when binding happens it causes a displacement of the regulatory protein (hsp90) which exposes a DNA binding domain

Question 2

Describe the effects of allosteric modulators on ion channels and GPCRs

Answer 2

Ion channels

GPCRs

Question 3

Describe the features of G protein activation
G-protein cycle

Answer 3

-Before the cycle starts the alpha subunit is bound to a GDP
-To start the cycle the ligand will bind to the receptor which induces a conformational change that causes alpha subunit to release GDP and bind GTP (this binding of GTP thus activates the subunit)
-The now active alpha bound to GTP releases from the beta and gamma subunit
- now release the beta and gamma are not active as well
- eventually the alpha GTP will hydrolyze the GTP to GDP which will cause it to re-associate with the beta and gamma subunit and this will thus reset the cycle

Question 4

compare signaling of the second messengers and arrestin

Answer 4

Second messengers
- cAMP, Phosphoinositides
The ligand must bind to the receptor for anything to happen
the receptor will then trigger the activation of a G protein located on the cytoplasmic face of the plasma membrane
1. cAMP
- Enzyme is adenylyl cyclase converts ATP to cAMP

Arrestin
invovled in desensitization
endocytosis
signaling

NOT DONE

Question 5

Describe the mechanism and consequence of receptor desensitization

Answer 5

mechanism

Consequences
- can decrease receptor and G protein coupling

Question 6

Assess ligand-receptor concentration response curves for functional selectivity

Answer 6

Requires that the receptor couples to multiple signal transduction pathways

Question 7

Use the concept of functional selectivity to design better drugs

Answer 7

Functional selectivity is the selectivity for different signaling pathways coupled to the same receptor
In order to have functional selectivity the receptor must bind to multiple pathways and it must have a preference for one pathway over the other
Tirzepatide- weight loss drug is functionally selective

Question 8

who discovered cyclic AMP (cAMP)

Answer 8

Earl Wilbur sutherland

Question 9

Cell surface receptors and signal transduction pathways HINT there is 2
(Describe it and show one example)

Answer 9

need more info

Question 10

Ion channels
voltage gated channels
(Describe it and show one example)

Answer 10

• Regulated by depolarization and hyperpolarization through phosphorylation & G-proteins
• Sodium, calcium, and potassium channels

Question 11

Ion channels
Ligand gated channels
(Describe it and show one example)

Answer 11

Regulated by ligands and have ligand binding domains
Usually have 2 ligand binding receptors
work by changing membrane potential of the cell
- This is because when the channel opens it allows the flow of ions in and out
These are very fast receptors and that is crucial for rapid transfer of signals across the synapse
EX)
1. Gaba-a receptor
-conducts chloride
-When the chloride flows into the cell it hyperpolorizes it
The receptor is made of 5 subunits and has 2 binding sites for its orthosteric agonist gaba
It has allosteric sites as well
2.NMDA receptor
- Regulated by phosphorylation which can increase or decrease activity
- Binds to glutamate as its orthosteric ligand
- comprised of 4 transmembrane helices
- Positive ions come into the cell and depolorize it
- has allosteric binding sites as well

Question 12

GPCRs
(Describe it)

Answer 12

Inrtacellular C terminal tail that has many hydroxyl residues around it
- These hydroxyl residues end up getting phosphorylated by kinase
Has an extracellular N terminus
How it works?
- agonist binds to the orthosteric site
-This binding causes a conformational change that allows it to interact with the G-protein
- G proteins are lipidated which keeps them by the membrane and near the receptor

Question 13

G-alpha(s)

Answer 13

Stimulate Adenylyl cyclase
Stimulate Src family tyrosine kinases

Question 14

G-alpha(i)

Answer 14

Inhibit Adenylyl cyclase
stimulate phosphodiesterases

Question 15

G-alpha(12/13)

Answer 15

Rho guanine exchange factor (recruit)

Question 16

G-beta,gamma

Answer 16

inhibit Adenylyl cyclase
recruit GRK2 and 3
Stimulate PI2K gamma
stimulate Ion channels (Ca2+ and K+)

Question 17

G-beta(5)

Answer 17

G-beta(5) is structurally different but 1-4 are very similar

Question 18

G-gamma (12)

Answer 18

show unique behaviors

Question 19

G-alpha(q)

Answer 19

stimulate phospholipase C

Question 20

What is the importance of GPCRs

Answer 20

They are important because they are involved in taste, sense, smell, sympathetic and parasympathetic nervous functions, metabolism, immune regulation, and reproduction