Chapter 2: Drug Receptors

Question 1

Activation of a GPCR protein

Answer 1

1. Ligand binds to GPCR orthosteric site extracellularly
2. Protein is conformationally changed
3. Alpha subunit is activated: switches GDP for GTP
4. Alpha subunit dissociates from beta-gamma subunit
5. Alpha subunit regulates target proteins
   -target protein relay signal via secondary messenger (ex. ATP->cAMP)
6. Alpha subunit deactivated a by phosphorylase (GTP back to GDP)

Question 2

Describe Cell Signaling Process

Answer 2

1. Signaling cell releases a signaling molecule
2. Signaling molecule travels through a gap, binds to an inactive cell surface receptor, which activates it
3. Causes a signal transduction cascade
4. Activates the effector protein
   -final protein in the cascade that’ll elicit the effect

Question 3

Describe Phosphorylation Cascade

Answer 3

1. Drug binds to receptor
2. Activates a protein kinase (PK1)
   -Kinases add a phosphate group to active protein
   3.PK1 then activates PK2, so on and so for
   -1 activated receptor can multiply response (1 activates 10, those activate 100…)
   -phosphatase removes a phosphate group
3. Eventually effector protein is activated which elicits the cellular response

Question 4

Orphan receptor

Answer 4

Found a receptor but don’t know what binds to it yet

Question 5

7-Transmembrane receptor/GPCRs

Answer 5

G-protein-coupled receptors
-Biggest group of receptors that we use to target w/ drugs
-7 transmembrane alpha helices
-Heterotrimeric (alpha, beta, gamma)
-GDP (inactive) vs. GTP (Active)

-Amino acids within cell membrane: Hydrophobic
-Amino acids at cell membrane surface: Hydrophilic

Question 6

Ligand-gated Channels

Answer 6

-Open when something binds

Two Types:
1. Inotropic:
- Ligand binding site & channel are the on same protein
- nACh receptor

2. Metabotropic:
   - Ligand activates a GCPR which results in a secondary messenger that opens the channel

Question 7

Catalytic Receptors

Answer 7

-Membrane bound, ligand activated

-Cytoplasmic catalytic domain
a. Enzymatic rxn that occurs within them that changes downstream effects when ligand binds (ex. kinase, phosphatase)

-Examples: tyrosine kinase, tyrosine phosphatase, etc.

Question 8

Describe Desensitization Molecular Response- GRK

Answer 8

1. Drug binds to receptor causing -OH group arm to swing outward/change shape
2. Now the GPCR (alpha subunit) can attach to receptor and have its effect
3. G-receptor kinase (adds phosphate group) targets receptor itself and removes -OH group & phosphate groups attach to those spots
   A. Original drug still bound to receptor
4. Beta- arrestin “arrests” (stops) the signaling and binds to the phosphate groups
5. Beat- arrestin takes it to a clarithin protein area
6. Entire structure (protein, drug, phosphate groups) pinches inward turns into clarithin coated pit inside the cell
   A. Turns off the signal
7. Two different pathways to get rid of bound interaction
   A. Lysosome- kills it and recycles into amino acids
   B. Peroxisome- changes pH inside CCP could lead to drug coming of receptor

Question 9

What is desensitization?

Answer 9

• Way of shutting down a response
• Give a dose of drug but after awhile the response decreases over time; eventually barely seeing a response even with the same dose of drug
• Off period (D/C drug): Then restart and see response and then see desensitization again

Question 10

Role of Secondary Messenger

Answer 10

Setup of a second cascade of events

-Most Common:
cAMP (cyclic), cGMP, IP3 (inositol triphophate), DAG (diacylglycerol), Calcium

Question 11

4 Types of Transmembrane Signaling

Answer 11

1. Intracellular Receptors: Receptor within cytoplasm, occurs with lipid drugs soluble (Uncharged drugs- Steroids)
2. Cell Surface Receptors
   A. Ion Channels: Inotropic vs. Metabotropic, Voltage gated
   B. Catalytic: enzymatic change
   C. GPCRs

Question 12

Receptor Tyrosine Kinase

Answer 12

-Ligands: Growth Factors or Adhesion molecules
a. Development to occur or structural changes of organ

-When Ligand Binds,
a. Dimerization: Needs 2 of the same ligand to join together to cause activation
b. Phosphorylation (adding phosphates) of tyrosine residues
c. Anchoring site for a ton of downstream signaling molecules

Question 13

Voltage Gated Channels

Answer 13

A. Found in excitable cell

B. Respond to changes in voltage
-Usually closed at resting membrane potential

C. Based on ion selectivity
-Sodium gate (heart rhythm)

Question 14

Intracellular Receptor

Answer 14

Need to be able to cross cell membrane to act on receptor within cell
A. Gasses
B. Lipid soluble Agents (steroids)- steroid receptor take along to take effect

Example) High BP/Increased of blood flow
1. Shearing force cause release of Ca+
2. Ca+ activates nitric oxide synthase (NO is gas can’t be store, so only made when needed- Arg)
3. NO crosses into smooth muscle reacts w/ GTP and guanylyl cyclase to make cGMP (relaxes smooth muscle)