VOC - Molecular Pharmacology II

Question 1

What percentage of genes in the human genome encode G-protein-coupled receptors?

Answer 1

Approximately 3-5% of genes in the human genome encode G-protein-coupled receptors

Question 2

Name the 5 families of G-protein-coupled receptors?

Answer 2

Family 1 - Rhodopsin

Family 2 - Secretin

Family 3 - Glutamate

Family 4 - Frizzled/TAS2

• Have distinct ligands compared to other families

Family 5 - Adhesion

Question 3

What are adrenaline activating alpha 1, alpha 2 and beta receptors responsible for?

Answer 3

Alpha-1: Smooth muscle contraction

Alpha-2: Inhibition of transmitter release, smooth muscle contraction

Beta: Heart muscle contraction, smooth muscle relaxation, glycogenolysis

Question 4

What are the pharmacological consequences of activating different receptor subtypes?

Answer 4

Beta-1 in the heart (Propranolol):

• Tachycardia.

Beta-2 in airways (Salbutamol):

• Asthma.

Alpha-1 (Prazosin):

• Hypertension.

Alpha-2 (Yohimbine):

• Memory retrieval, blood pressure boost, Inhibits neurotransmitter release

Question 5

What are the 4 receptor subtypes and how are they activated?

Answer 5

→ G-protein coupled receptors:
Transduces and interacts with an intracellular G-protein, downstream response

→ Ligand-gated ion channels:

→ Receptor tyrosine kinase: Phosphorylation
→ Steroid:
Diffuses and binds to intracellular protein causing changes in cell signalling
Change in gene expression

Question 6

How can structure-function of receptors be studied?

Answer 6

1.

• Express cDNA for receptor
• Measure activity
• Normal structure function

2.

• Express mutated receptor cDNA
• Resulting receptor is different
• If different activity you have modified structure function

Question 7

How are G-protein coupled receptors activated? (5)

Answer 7

1. Upon activation, off receptor changes its conformation
2. G-protein trimer made of alpha, beta and gamma subunits
3. Releases GDP on alpha and binds GTP
4. Alpha subunit loaded with GTP splits from beta and gamma
5. GTP hydrolysed and GDP alpha returns back to its original state

Question 8

What is the main structural feature of g-protein coupled receptors and its method of transduction?

Answer 8

Seven transmembrane-spanning domains

Bind agonist supplied from outside

Alter receptor conformation

Make contact to activate G-protein

Question 9

Check notes for description on each individual family of GPCRs

Question 10

What are the key features of the agonist binding site in Adrenergic GPCRs?

Answer 10

2 x Serine on transmembrane V

• 2 x-OH on Catechol group bind to 2x -OH on Serines

1 x Aspartate on transmembrane III

• -COOH on aspartate binds to -NH2 on Catechol group

Question 11

How do GPCRs respond to agonist binding.

Answer 11

Changes conformation and creates opening at the bottom of the receptor, producing a G-protein binding site

• Agonist bind moves helices (5 and 6)
• G-protein binds stabilizes change in helices conformation