Receptor Families

Question 1

What is a receptor

What does it do

Answer 1

• A receptor is a bifunctional molecule (principal drug target)
• It recognises ligands which reversibly bind to a site and the combination of ligand with receptor triggers a response

Question 2

What are the 4 receptor superfamilies

Answer 2

• Ion channels
• G-protein-coupled receptors (metabotropic receptors)
• Kinase-linked receptors
• Steroid receptors (IC receptors)

Question 3

What are GPCRs also known as

Answer 3

Metabotropic receptors

Question 4

What are steroid receptors also known as

Answer 4

IC receptors

Question 5

What do VG Ca2+ channels in the heart and BVs influence

Answer 5

Heart rhythm and constriction of BVs

Question 6

In terms of drugs, what are VG Ca2+ channels a target for (2 points)

Answer 6

1. Anti-dysrhythmics (verapamil)
2. Anti-hypertensives (amlodipine)

Question 7

What blocks VG Na+ channels

Answer 7

Local anaesthetics

Question 8

What is another name for ligand-gated ion channels

Answer 8

Ionotropic receptors

Question 9

What is a ligand

What happens when a ligand binds to its site on the receptor

Give an example

Answer 9

• A ligand is a small molecule that binds to a receptor
• It causes conformational change, opening the channel and allowing ions to flow through
• Nicotinic receptors to which the endogenous ligand ACh binds

Question 10

How are ligand gated ion channels activated

Answer 10

By binding of chemical ligand to a site on the channel molecule

Question 11

Give an example of a ligand-gated ion channel

Explain how it works

Answer 11

Nicotinic ACh receptor

• Nicotine binds and activates the receptor
• Allows Na+ and Ca2+ into the cell
• Stimulant in CNS causes enhanced NT release
• Also causes release of adrenaline from adrenal gland - fight or flight response

Question 12

What is nicotine in terms of the ACh receptor

Answer 12

A drug that is an exogenous ligand for the ACh receptor

(ACh is the naturally occuring endogenous ligand for this receptor)

Question 13

Where does the endogenous ligand ACh bind to the nicotinic receptors

What happens as a result

Answer 13

• ACh binds to a site on the alpha subunits opening the channel and allowing Na+ ions to pass through the membrane

Question 14

Define diazepam

MOA of diazepam

Answer 14

• a benzodiazepine receptor agonist

Question 15

What is the most abundant class of receptors

What are they also known as

Answer 15

G-protein-coupled receptors

Metabotropic receptors

Question 16

What is the structure of GPCRs/metabotropic receptors

Answer 16

7 transmembrane helices (heptahelical), with EC domain usually containing the ligand-binding region

Question 17

What do GPCRs/MRs possess

Answer 17

IC regions that activate G protein signalling molecules (as they bind the guanine nucleotides GTP and GDP)

Question 18

What do GPCRs/MRs do

Answer 18

Activate the production of 2nd messengers (cAMP, diacylglycerol/DAG and inositol-1, 4, 5-triphosphate/IP₃)

Question 19

Give an example of a GPCR/MR

Answer 19

Beta-adrenoceptors: adrenaline/noradrenaline is endogenous ligand (3 subtypes - B₁, B₂ and B₃)

Question 20

What is the effect of activation of GPCRs

Answer 20

Phosphorylation of proteins - on/off

Question 21

What happens when beta-adrenoceptors in the heart are activated

Answer 21

• Phosphorylates VG Ca2+ channels
• Causes the channel to open & Ca2+ comes into the cell
• Contracts heart muscle
• Beta blockers prevent this effect

Question 22

What do beta blockers do

Answer 22

Prevent activation of beta adrenoceptors in the heart => no phosphorylation of VG Ca2+ channels and Ca2+ does not come into the cell

Question 23

What are G proteins composed of

What does the G protein act as

Answer 23

3 subunits - α, β, γ (heterotrimeric)

G protein acts as the interface between the receptor and the enzymes and/or ion channels that are ultimate targets of GPCRs

Question 24

Where is there a binding site for GDP/GTP

What happens when it is occupied by GTP

Answer 24

There is a binding site for GDP/GTP on the α subunit

When this is occupied by GTP, the α subunit separates from the other subunits => inactive when GDP is bound

Question 25

G protein coupled receptor structure

Answer 25

Question 26

The series of events once the ligand binds to the G protein coupled receptor

Answer 26

\* G protein has an affinity for GDP when not associated with the receptor \* Effector proteins are embedded in the membrane or IC 1. Ligand binds 2. G protein association - exchange of GDP for GTP on a subunit 3. α subunit dissociates and interacts with effector molecule 4. Effector molecule activates secondary messengers 5. Return to resting state following activation of effector molecule

Question 27

Name the endogenous ligands of the GPC B2 receptor

Answer 27

Adrenaline & noradrenaline

Question 28

What are kinase-linked receptors also known as How many membranes do they span How do they cause an effect within the cell What are these receptors involved in Give an example

Answer 28

* Receptors with enzymatic cytosolic domains * Single membrane spanning proteins * Cause an effect within the cell by adding or removing phosphate groups to or from specific AA residues * Many of these receptors are involved in growth and differentiation * e.g. insulin receptors (a member of the tyrosine kinases, the largest group)

Question 29

What must tyrosine kinases do in order to produce their effect

Answer 29

They must associate & form a dimer

Question 30

Within the action of tyrosine kinases, what happens once a dimer is formed

Answer 30

Phosphorylation of tyrosine residues on effector proteins

Question 31

Explain how insulin is an example of a tyrosine kinase

Answer 31

* Promotes uptake of glucose from blood into cells for storage (e.g. as glycogen in liver) * Phosphorylates and activates enzymes that synthesise glycogen, and inactivates enzymes that break down glycogen to glucose

Question 32

What are NUCLEAR receptors also known as

Answer 32

IC receptors

Question 33

What is the criteria for the ligand of nuclear/IC receptors

Answer 33

Must be lipid soluble in order to penetrate the membrane

Question 34

Inactive forms of nuclear/IC receptors that are present in the cytosol or nucleus are associated with...

Answer 34

Transcription regulatory factors

Question 35

What happens to nuclear/IC receptors once the ligand binds What does it affect Give an example

Answer 35

* Migrate to nucleus when the ligand binds * Affects DNA, altering gene transcription and thus translation of RNA into protein * e.g. steroid receptors

Question 36

Explain the steps in the MOA of nuclear/IC receptors

Answer 36

1. Ligand enters cell 2. Ligand binds 3. Ligand-receptor complex enters nucleus, dimerises and binds to DNA and thus altering cellular protein expression

Question 37

Transcription =

Answer 37

DNA makes RNA

Question 38

Translation =

Answer 38

RNA makes protein

Question 39

What effect do steroids have on transcription give an example what is the response time

Answer 39

* Activate or inhibit transcription * e.g. glucocorticoids inhibit transcription of gene for cyclo-oxygenase-2 (COX-2) * Anti-inflammatory * Slow response because of time to make or destroy proteins

Question 40

Receptor summary

Answer 40

Question 41

What are other drug targets besides receptors

Answer 41

* Ion channels * Enzymes * Transporters