1-3,4 - Target sites

Question 1

Give the time frame for 4 types of receptors

Answer 1

• Ligand-gated ion channels (ionotropic receptors) - miliseconds
• G protein-coupled receptors (metabotropic) - Seconds
• Kinase-linked receptors – Hours
• Nuclear receptors - Hours

Question 2

Describe ligand-gated ion channels?
- How they work?

Answer 2

Ligand binds to receptor.
Receptor opens channel and allows ions to flow through leading to depolarisation/hyperpolarisation.

Question 3

Describe GPCRs
- Structure
- How they work? Reset how?

Answer 3

7 transmembrane domains. Couples to G proteins. G proteins are heterotrimers.
- Molecules bind to GPCR
- G-protein binds to receptor
- Alpha subunit of G-protein exchanges GDP for GTP, beta-gamma subunit dissociate.
- G-protein now active for downstream effects.
- Reset when hydrolyse own GTP and associate subunits back.

Question 4

Describe kinase-linked receptors
- How they work?
- 2nd messenger

Answer 4

Ligand causes phosphorylation of intracellular domain and downstream effects.
- Usually two receptors near one another. Signal molecule causes dimerisation of receptors causing tyrosine residues to phosphorylate, leading to downstream effects.
- Effects include gene transcription for growth factors, cytokines, and hormones.
- These are tightly regulated

Question 5

Types of kinase-linked receptors based on location?
- Mechanism differences?

Answer 5

Class 1 – Activates a transcription factor in the cytoplasm which then moves into nucleus.

Hybrid – Bind to steroid receptor in cytoplasm which then releases its inhibitory component so receptor is small enough to enter nucleus.

Class 2 – Ligand binds to receptors within nucleus.

Question 6

1) What general effect to the response does an agonist have?
2) Antagonist effect?
3) Types of agonists?
4) Can antagonists have affinity or efficacy?

Answer 6

1) Increase or decrease
2) No response/prevent response.
3)
- Full agonist = Produce max effects
- Partial agonist = Produce not max effects even if all receptors activated
- Inverse agonist = Bring receptor to resting state (decrease reponse). Bind to different site.
4) Only affinity (no efficacy)

Question 7

Effect of competitive reverse antagonist presence on dose-response curve of agonist?

Answer 7

Shift to the right

Question 8

Effect of competitive irreversible antagonist on dose-response curve of agonist?

Answer 8

Lower max efficacy. Due to antagonist having higher affinity for receptors.

Question 9

Effect of non-competitive antagonist on dose-response curve of agonist?

Answer 9

Shift right and lower max efficacy.

Question 10

Describe the 2 possible adenylyl cyclase pathways

Answer 10

G alpha s (stimulatory):
- Adenylase binds to GPCR
- G protein forms cAMP
- cAMP activates protein kinases
- downstream effects
G alpha i (inhibitory):
- Above but inhibits adenylyl cyclase

Question 11

Describe the Phospholipase C pathway

Answer 11

G alpha q:
- Alpha exchange GDP for GTP.
- PIP2 gets cleaved into 2 (being DAG and IP3)
- DAG remain on cell membrane whilst
- IP3 binds to IP3 gated Ca2+ channels at ER
- Ca2+ released from endoplasmic reticulum.
- Ca2+ binds to Protein Kinase C (PKC), activating it, causing it to anchor to DAG on cell membrane.
- Active PKC (since it binded to DAG) has downstream effects via phosphorylation of substrates.

Question 12

Describe receptor tyrosine kinases

Answer 12

• 2 growth factors bind against 2 receptors total
• The 2 receptors dimerises
• This autophosphorylates the receptors
• This recruits Grb2 which then gets phosphporylated.
• This activates Ras which leads to phosphorylation cascade that leads to gene transcription.

Question 13

Describe cytokine receptors

Answer 13

• 1 Cytokine causes receptors to dimerise
• Jak which is attached to receptors will phosphorylate itself and the receptor
• Stat is recruited but required dimerisation (2 stats) before it can affect gene transcription

Question 14

Describe how nuclear receptors work

Answer 14

• Lipophilic ligands cross cell membrane
• If receptor in cytoplasm, ligand binding causes HSP complex displacement which allows receptor to travel into nucleus. Now receptors dimerise and thus activate.
• Otherwise, if receptor in nucleus, ligand travels there and then causes receptor to dimerise and thereby activate.

Question 15

3 ways of controlling an ion channel?
- Types of gating?
- How can the ligands modulate it?

Answer 15

• Ligand-gated
• Voltage-gated
• Calcium release channels (ER)

Ligands either modulate (increase or decrease ion permeability) or block it (ions can’t flow through)

Question 16

How can enzymes be used as a drug target (3 things)?

Answer 16

Inhibition – Binding site covered with drug, prevents normal reaction.
False substrate – Drug acts as substrate but creates different product
Prodrug – Enzyme will activate drug.

Question 17

Describe how neostigmine works to improve muscle tone.

Answer 17

It inhibits acetylcholinesterase by binding to it, preventing acetylcholine from binding to it and thereby breaking down. Increases ACh total amount.
- Used to treat myasthenia gravis
- Increases muscle activity.

Question 18

What’s Codeine

Answer 18

Adrenaline pro-drug to bypass liver.