Drug Receptors (Exam 1)

Question 1

What is a receptor?

Answer 1

a component that interacts with a drug and initates a chain of events leading to the drugs observed effects

Question 2

What are the factors in receptor concept?

Answer 2

1. receptor affinity determines dose given by kd(50% of receptor bound)
2. receptor selectivity varies per drug
   - selective for single receptor or multiple
3. receptor activated(agonist) or blocked(antagonist) can be activated if nothing is bound

Question 3

What is the Nature of Receptors (4)

Answer 3

They are proteins that have long chains of AA
regulatory: transcription/translation
enzyme: stop a process or speed up
transport
structural

Question 4

What are orphan receptors?

Answer 4

receptors that have no known endogenous ligand about half (500) in the body

Question 5

What is the most important receptor?

Answer 5

Seven-transmembrane receptor
- G-Protein Coupled Receptor GPCRs
- 2/3 of non abx drugs bind to this

Question 6

What are ligand-gated ion channels?

Answer 6

open a channel if something binds to them

Question 7

Explain Cell SIgnaling

Answer 7

1st messenger: signaling molecule (drug or end ligand)
2: receptor where ligand binds
3. signal transduction proteins: produce 2nd messengers and vary (cAMP,IP3, DAG)
4. Activate effector proteins and produce change in the cell

Question 8

What are ion channel receptors?

Answer 8

doesnt need a ligand, open because theres a change in charge in the membrane

Question 9

What is a Lag period?

Answer 9

Receptors take a while to see a response
seen in transctiption and translation
production of mRNA and protein from mRNA
take hours, days, weeks

bacteria is faster

Question 10

What is persistence of a drug?

Answer 10

Drug given once and last a long time until proteins pathways degrade

Question 11

Compare linear response to multiply response to coupling

Answer 11

Response can be huge or focused related to how many receptors are bound
Linear: single receptor binds to drug response needs more receptors
Transduction cascade: activate a protein activate more proteins etc.

Question 12

Draw and explain the phosphorylaiton cascade

Answer 12

Drug binds to receptor
conformational change
can activate protein kinase
active protein kinase can phosphorylate protein-1
which can phsophorylate protein 2 etc..
end activate effector

Question 13

What is the mechanism of intracellular receptors

Answer 13

Drug has to be lipid soluble to cross the membrane and bind to the receptor or find a way to get into the cell

Question 14

Name three cell surface receptor and what they do

Answer 14

Ion channels: durg binds to the receptor and open
Catalytic: receptor becomes an ezyme and activates or activates a protein and additional enzymes (phosphorylation cascades)
GPCRs: receptor is attached to a g-protein
- goes and activates an enzyme phosphorylation cascade or 2nd messengers

Question 15

What are GPCRs

Answer 15

Receptor coupling activates G-protein
- G-protein is guanine nucleotide binding protein (GTP)
- can activate hundred of g-proteins
2/3 of all non abx drugs are GPCRs
500 identified, 500 orphan

Question 16

What is the structure of a GPCR

Answer 16

protein have animo and carboxy terminal end
crosses the membrane 7 times
outside active site; inside g-protein site
G-proteins are trimeric (alpha, beta, gamma)
- alpha is important binds to GDP(inactive) or GTP (active)

Question 17

What kind of response can GPCRs produce in relation to speed

Answer 17

Fast- ion channels, enzyme, rapid desensitization
slow- transcription factor activation

Question 18

Identify some 2nd messengers (5)

Answer 18

cAMP (most common)
cGMP
Ca2+
DAG
IP3

Question 19

Describe the activation of GPCRs and 2nd messengers (adenylyl cyclase)

Answer 19

1: 1st messenger (endogenous ligand/drug) binds to the g-protein receptor
2. g-protein is inactive and bound to GDP becomes activated and GDP falls of and GTP binds activates the alpha subunit of the g-protein
3. alpha subunit activates the effector protein
4. Adenylyl Cyclase (effector protein) cyclates ATP to cAMP (2nd messenger)
5. cAMP activates protein kinase A
6. cellular response

Question 20

Explain G proteins and Phospholipase C

Answer 20

1: 1st messenger (endogenous ligand/drug) binds to the g-protein receptor
2. g-protein is inactive and bound to GDP becomes activated and GDP falls of and GTP binds activates the alpha subunit of the g-protein
3. alpha subunit activates the PLC
4. PLC targets phopholipids in the. cell membrane PIP2 (2nd messenger)
6. PIP2 is cleaved to DAG and IP3 (2nd Messenger)
7. IP3 binds to receptors in the ER
8. ER releases Ca2+ (2nd messenger) proteins activated
9. cellular response

Question 21

Explain the concept of “Desensitization”

Answer 21

give an agonist continously overtime and gets a muted response
stop giving agonist returns to constituitive activity
give agonist again peaks then declines over time

Question 22

How does desensitization occur in GPCRs?

Answer 22

1. Ligand binds to receptor and changes shape to open conformation and three AA at the end of the receptors have OH groups
2. releases alpha subunit to be activated then signaling cascade
3. drug is covalently bound to receptor and the OH groups are exposed for a while (phosphorylated) the protein beta-arrestin binds and blocks further activity
4. beta-arrestin interacts with chlatherin coated pit (endocytosis)
5. receptor+ drug+beta arrestin goes into the cell
6. drug can detach and receptor can move back to cell surface (recycling)
7. drug+receptor bond cannot break so it fuses with lysosome and degrade the receptor
8. Drug doesnt degrade just removed unless its a protein

Question 23

What are Catalytic Cell-Surface Receptors?

Answer 23

membrane bound and ligand activated
has enzymatic component ; associated or receptor is an enzyme

example RTKs

Question 24

Differnetiate between kinase and phosphatase

Answer 24

Kianses: phosphorylate
Phosphatases: take away phosphate

Question 25

What ligands bind to Receptor Tyrosine Kinases (RTKs)

Answer 25

growth factors and adhesions factors (WBCs)

Question 26

How does RTKs get activated

Answer 26

1. 2 ligands bind to 2 monomer and form a dimer
2. dimerization causes phosphorylation (6 ATP)
3. active form of receptor interacts with effector proteins
4. then downtream effects

no associated g-protein, receptor itself makes phosphate groups and activates effector proteins

Question 27

What are Ion Channels

Answer 27

Pores in the cell membrane that allow highly charged molecules to cross (Na,K,Ca,Cl)
Transmembrane potential governed by ion channels

Question 28

Where are voltage gated channels found and how do they work

Answer 28

found in cells that are excitable (neurons, muscle, endocrine)
closed at resting membrane potential
Specificity: depends Na, Ca, Na
closer to the threshold gates open and activate (gate 1) ion goes into the cell (high to low)
inactivation: gate 2 closes
deactivation: both gates shut
back to closed

change voltage opens them

Question 29

What is a ligand gated ion channel and what types are there

Answer 29

ligand binding site to open
ionotropic (more common)
-binds and becomes activated
metabotropic
-GPCR near ion channel and activation of GPCR opens the ion channel

Question 30

What is an example of a ionotropic ligand gated ion channel

Answer 30

Nicotinic Ach receptor found in skeletal muscle, takes 2 Ach to open, Na floods in, Na opens Ca channel inside cell, muscle contraction

Question 31

What is an example of a metabotropic ligand gated ion channel

Answer 31

odor molecule binds to a GPCR and activates g-protein to activate effector protein making 2nd messenger binds to ion channel and opens

Question 32

How are receptors inside the cell activated

Answer 32

Drug or gas that is lipid soluble

Question 33

Example of NO activating receptors inside the cell

Answer 33

blood shearing endothelium activates NOS to make NO diffuses into smooth muscle binds and activates guanylyl cyclase turn GTP to cGMP causing relaxation opening the blood vessel lowering overall BP

Question 34

How do steriods activate receptors inside the cell?

Answer 34

Steroid hormones uncharged and freeely diffuse and target receptors inside the cell
transmigrates into the nucleus and binds to steroid regulaltory elements and increase transcription and translation