W3- Lecture 13.2- Receptors (pharma)

Question 1

What percentage do G-protein coupled receptors represent of total drug action?

Answer 1

30%

Major focus on drug discovers as “good drugable targets”

Question 2

What is topology ?

Answer 2

Shape

Question 3

Define domain

Answer 3

Part of a protein, which can be defined by 3D shape

Question 4

Describe the topology of a GPCR

Answer 4

7 transmembrane domains
Ligand binding domain
Domain(s) to interact with G-protein

Question 5

Describe the topology the beta 2-adrenergic receptor

Answer 5

7 Transmembrane domains that forms channel
Resolved by X-ray crystallography

It has regions
To interact with g-proteins
That bind with agonists and antagonist
That are involved in desensitisation

Question 6

Describe desensitization of a receptor

Answer 6

Offer long periods of activation receptors become less active

Question 7

Describe G protein activation

Answer 7

1) ligand binds with receptor
- conformational change in the alpha beta and gamma complex allowing GTP to bind instead of GDP
2) Alpha dissociates from the beta and gamma complex
3) alpha coupled to GTP then associates with adenyl cyclase / target enzyme
4) GTPase hydrolyses GTP into GDP
- this inactivates then enzymatic activity of the alpha subunit while activating target enzyme (adenyl cyclase)
5) activation of adenyl cyclase converts ATP to cAMP(which is a secondary messenger)
5) inactive alpha subunits rejoins the beta gamma complex

Question 8

what do the g alpha subtypes after activation do ?
+example

1) G(alpha)i/o
2) G(alpha)S
3) G(alpha)q

Answer 8

1-G(alpha)i/o
inhibits adenylate cyclase
ACh acting at M2/M4 receptors)

2- G(alpha)S
stimulates adenylyl cyclase
eg. adrenaline acting at beta-adrenoceptors

3)G(alpha)q
stimulates inositol phosphate turnover
muscarine acting at M1, M3 and M5 mAChRs
inositol phosphate activates protein kinase as increased concentration of calcium ions within the cell

Question 9

Inositol Phosphates
Method of Ca2+
Important cellular activites that involve Ca2+

Answer 9

InsP3 binds to endoplasmic receptors and opens endoplasmic Ca2+ channels
Ca2+ now in cytosol

Important events

• Muscle contraction
• control of secretion from exocrine glands
• hormone release

Question 10

Some ion channels are regulated by GPCRs

Describe this action

Answer 10

G beta gamma complexes directly interact with channels

e. g. mAChRs increase K+ channel activity in cardiac muscle
e. g. Gbetagamma subunits can inhibit voltage-sensitive calcium channels in neurones (leading to reduced neurotransmitter release).

Question 11

Describe tolerance and desensitisation

Answer 11

Tolerance is where receptors are stimulated for too long the receptors need a higher concentration / the drug becomes less potent
Desensitisation is shorter term than tolerance when the activation is decreased

Question 12

Describe what happens to receptors when they are over/under stimulated

Answer 12

Both a slow responses
If the receptors are being over-stimulated the number of recptors will increase however they may be less sensitive

If they ate being under stimulated the number of receptors will decrease however the sensitivity may increase