Molecular targets 1: GPCRs & nuclear receptors

Question 1

What is a G protein coupled receptor GPCR

Answer 1

• Seven transmembrane domains
• Coupled to G protein to initiate signal transduction
• Activated by diverse signals e.g. photons, hormones, peptides etc.

Question 2

How many drug targets use GPRC as a receptor

Answer 2

More than 50%

Question 3

GPCR classification - six categories

Answer 3

• Based on sequene homology and functional similarity
• Class A: Rhodopsin-like - Short N terminus
• Class B: Secretin-like - Larger globular N terminus
• Class C: Metabotropic glutamate/pheromone - very large N terminal domain binds against agonists
• Class D: Fungal pheromone
• Class E: cAMP receptors
• Class F: Frizzler/Smoothened
  Unclassified

Question 4

Majority of prescribed drugs are which class?

Answer 4

Class A e.g. b adrenoreceptors, histamines and dopamine receptors

Question 5

How are GPCRs activated?

Answer 5

1. Agonist binds to GPCR
2. Receptot changes shape - exposure to potential binding site
3. G protein couples to the receptor
4. Exchange of GDP for GTP
5. G protein moves apart leading to different signalling pathways via the βγ and Gα subunits

Question 6

What is desensitisation of GPCRs

Answer 6

• Its a regulatory process in which a cell reduces its response to a stimulus over time
• Crucial in preventing overstimulation
• Its achieved by phosphorylation or internalisation

Question 7

What are the two ways in which desensitisation of GPCRs occur?

Answer 7

• Homologous d: When specific GPRC stops responding to signals because the receptor has been phosphorylsed or internalised for degradation
• Heterologous d: When GPRCs stop responding because another receptor in the cell was activated

Question 8

Define tolerance in relation to drug action

Answer 8

• Tolerance is a progressive reduction in the effectiveness of a drug - occurs over hours or days
• Its a problem in HC like morphines long lasting effects can cause addiction

Question 9

What is enkaphines and morphine

Answer 9

• Enkaphines are small peptides which act as natural pain killers (opioids)
• Two pain types met-enk and leu-enk
• Morphine is an analgesic that activates opioid receptors

Question 10

What is biased agonism

Answer 10

• The ability of a drug to only activate some signalling pathways of a receptor

Question 11

Compare tolerance of enkephalins and morphines

Answer 11

• This explains why morphine has very long lasting effects
• Can cause addiction

Question 12

Structure of nuclear receptors

Answer 12

Question 13

How do nuclear receptors function

Answer 13

• Homodimers - two identical molecules come together e.g. two insulins
• OR heterodimers - two different molecules bind together

Question 14

Where are nuclear receptors located

Answer 14

• In the cytosol or nucleus not associated with lipid membranes
• They can also be referred to as ligand-activated gene regulatory proteins (transcription factors)

Question 15

Nuclear receptor classification

Answer 15

Thyroid receptor-like
Retinoid X receptor-like
Oestrogen receptor-like
Nerve growth factor IB-like
Steroidogenic factor-like
Germ cell nuclear factor-like

Question 16

Activators of nuclear receptors

Answer 16

• Small hydrophic molecules
• Must be transported in the blood stream
• Specific carrier proteins bind to increase solubility
• Dissociation occurs before entering the cell

Question 17

Binding proteins for transport and examples

Answer 17

• Thyroid hormone: globulin, albumin and transthyretin
• The steroid hormones: sex hormones

Question 18

Nuclear receptors: mechanism of action

Answer 18

1. Agonists bind to the ligand-binding domain and act as a molecular switch
2. A conformational change occurs within the receptor
3. Receptors dimerise and translocate to the nucleus

Question 19

Drugs targeting glucocorticoids receptors: dexamethasone

Answer 19

Question 20

Nuclear receptors: Targets for cancer therapy

Answer 20

Question 21

Tamoxifen

Answer 21