Pharmacodynamics - Receptor types

Question 1

What are drugs designed to target?

Answer 1

Regulatory proteins in existing cell signaling pathways

Question 2

What are 5 major classes of drug targets?

Answer 2

Membrane receptors
Nuclear receptors
Ion channels
Transport proteins
Enzymes

Question 3

In an inactive state, describe the setup of a GPCR

Answer 3

alpha subunit bound to GDP, as well as to the beta and gamma subunits

Question 4

Once the ligand binds the GPCR it is converted to its active state. Describe the setup

Answer 4

Alpha subunit dissociates from the beta and gamma subunits and binds GTP

Question 5

What subunit of the GPCR contains the gtpase activity?

Answer 5

Alpha subunit

Question 6

Gs

Answer 6

Activates Adenylyl Cyclase

Question 7

Gi

Answer 7

Inhibits Adenylyl cyclase

Question 8

Gq

Answer 8

Activates PLC

Question 9

G12/13

Answer 9

Activates RHO GTPases which then activates cytoskeleton rearrangements

Question 10

G proteins are classified based on?

Answer 10

Alpha subunit induced effects

Question 11

What occurs if the GPCR is active for a continued amount of time?

Answer 11

Desensitization = DECREASED cAMP

Question 12

If the agonist is removed quickly from the GPCR what will occur?

Answer 12

Resensitization - full response to a second agonist

Question 13

If downregulation occurs, where is the GPCR delivered?

Answer 13

Lysosomes

Question 14

What are the 3 new players in GPCR resensitization?

Answer 14

GRK
Beta-arrestin
Protein Phosphatase

Question 15

Describe how GPCR resensitization occurs

Answer 15

• GRK phosphorylates GPCR and prevents it from interacting with Gs
• Beta-arrestin binds the phosphorylated GPCR
• Beta-arrestin - GPCR complex binds to coated pits and is internalized
• Agonist dissociated from GPCR = decreased beta-arrestin affinity
• Protein Phosphatase dephosphorylates GPCR
• GPCR returned to plasma membrane

Question 16

Gs activates Adenylyl Cyclase. What does AC activate?

Answer 16

cAMP

Question 17

What hydrolyzes cAMP?

Answer 17

PDE

Question 18

Gq activates PLC. PLC then activates?

Answer 18

PIP2

- IP3 and DAG

Question 19

JAKs

Answer 19

Janus Kinases

Question 20

What types of ligands will activate JAK-STAT pathway?

Answer 20

Hormones and Cytokines

Question 21

When a cytokine binds to its receptor, JAKs are activated. What do JAKs do?

Answer 21

Phosphorylate and activate STATs

Question 22

Once 2 STATs are activated and phosphorylated by JAKs, what occurs?

Answer 22

They form a dimer and move to the nucleus to alter transcription

Question 23

When the JAK-STAT pathway is ON, what diseases occur?

Answer 23

Excessive inflammation

Autoimmune diseases

Question 24

What 3 things can JAK-STAT pathway INHIBITORS help control?

Answer 24

Rheumatoid Arthritis
Psoriasis
Inflammatory Bowel Disease

Question 25

Describe the JAK-STAT pathway

Answer 25

Cytokine binds to receptor JAKs activated JAKs phosphorylate and activate STATs STATs form dimers STATs go to nucleus and alter transcription = Control immune-mediated inflammatory diseases

Question 26

What ligands bind to Receptor Tyrosine Kinases?

Answer 26

GROWTH HORMONES | "GF"

Question 27

Growth Hormones bind?

Answer 27

Receptor Tyrosine Kinases

Question 28

Once 2 Growth Hormones bind a RTK at 2 locations, what happens?

Answer 28

2 RTKs will join to form a dimer = ACTIVE

Question 29

Once RTKs form a dimer, what happens?

Answer 29

Auto-phosphorylation of tyrosine residues

Question 30

Once Tyrosine residues are auto-phosphorylated, what occurs?

Answer 30

Their enzymatic activities are activated and they can phosphorylate other substrates

Question 31

What receptors are involved with RAS?

Answer 31

Receptor Tyrosine Kinases | growth hormones

Question 32

How is RAS activated?

Answer 32

- An adaptor protein binds to the phosphorylated tyrosine residues - A RAS activating protein binds to the adaptor protein and activates RAS GTPase - RAS is then bound to GTP and is active

Question 33

RAS activates?

Answer 33

Raf MEK ERK = cell cycle overstimulated

Question 34

Oncogenes often affect what type of receptor?

Answer 34

Receptor Tyrosine Kinases -- RAS pathway

Question 35

Nuclear receptors modulate?

Answer 35

Gene expression

Question 36

Ligands that bind to nuclear receptors must be ____

Answer 36

Lipophilic

Question 37

What type of ligands bind to nuclear receptors?

Answer 37

Steroids and hormones and Vitamins

Question 38

Nuclear receptors have a ligand binding domain, dna binding domain and transcription activating domain. What binds to the receptor in absence of a ligand to inactivate it?

Answer 38

Heat Shock protein 90 (HSP90)

Question 39

What causes the HSP90 to dissociate from the nuclear (glucocorticoid) receptor?

Answer 39

Binding of a ligand

Question 40

Glucocorticoid nuclear receptor activation causes?

Answer 40

Transrepression of NF-KB and AP-1

Question 41

Verapamil is an example of a drug that targets?

Answer 41

L-type calcium channels