MR S6 - Receptors & Membrane Turnover

Question 0

State a few roles of receptors

Answer 0

Signalling via:
Hormones
Neurotransmission
Cellular delivery
Ect

Question 1

What is a receptor?

Answer 1

A molecule which specifically binds to another molecule to illicit a change in a cellular process

Question 2

What is a ligand?

Answer 2

Any molecule that binds specifically to a receptor site

Question 3

What is an agonist?

Answer 3

A ligand which binds to a receptor and causes activation of that receptor

Question 4

What is an antagonist?

Answer 4

A ligand which binds to a receptor and doesn’t cause activation of that receptor

Question 5

What is signal transduction?

Answer 5

The transmission of a signal inside the cell when a ligand binds to a receptor on the cell surface

Question 6

How may a signal be transduced?

Answer 6

• Integral ion channels
• Integral enzyme activity
• Coupling to effectors through transducing proteins

Question 7

Why is signal transduction necessary?

Answer 7

To propagate the signal within the cell - hydrophilic ligands cannot pass the cell membrane so signal transduction is required

Question 8

Describe membrane transduction by integral ion channels

Answer 8

Agonist binding causes conformational change and the opening of a gated channel
Channel then permits the movement of ions down their concentration gradient
Eg classical nAChr and non classical Ryanodine receptors

Question 9

Describe membrane receptors with integral enzyme activity

Answer 9

Agonist binding to the extracellular domain causes conformational change
This activates an enzyme which form a part of the protein structure
Eg PDGF and linked tyrosine kinase

Question 10

Describe tyrosine linked receptors

Answer 10

Autophosphorylate upon ligand binding
Residues recognised by transducing proteins or directly by enzymes
Upon association, effector enzymes are activated which transduce the message into an intracellular chemical event
Eg insulin receptor

Question 11

Describe membrane bound receptors with transducing proteins

Answer 11

This family of receptors are known as GPCRs
7 transmembrane domain receptors couple to effector molecules via a transducing protein: a GTP binding regulatory protein or G protein
Effectors may be enzymes or ion channels

Question 12

What is integrated signalling?

Answer 12

When separate GPCRs act simultaneously to stimulate or inhibit an effector
The two inputs combine to produce a measured effect

Question 13

Give examples of GPCRs

Answer 13

Dopamine receptors, mAChR, 5-HT receptors and light, smell and taste receptors

Question 14

Describe the specificity of GPCRs in relation to their distribution

Answer 14

Very specific
Several GPCRs can exist for the same agonist
Eg M1-5 ACh receptors - each type are found in different locations.
Useful as drugs can be targeted at one type of GPCR to only affect a local area.

Question 15

Give examples of hormones with intracellular receptors

Answer 15

Hydrophobic hormones eg:
Oestrogen
Testosterone
T3 & T4
Cortisol

Question 16

Describe binding to intracellular receptors

Answer 16

Hydrophobic ligands pass through the cell membrane
Bind to intracellular receptors (in resting state these are bound to heat shock or chaperone proteins)
Activated receptor dissociates from it’s stabilising protein and moves to the nucleus where it binds to control regions in DNA

Question 17

What is a disadvantage of intracellular receptors?

Answer 17

They bind to DNA so they change translation and/or transcription therefore they have a slower effect than extracellular receptors

Question 18

How does amplification of signalling molecules occur?

Answer 18

Many ways eg
Stimulation of an enzyme can cause the binding of a single molecule to be amplified to hundreds or thousands of molecules
Enzyme cascades can be triggered, causing further amplification

Question 19

Why may amplification of cellular signals be necessary?

Answer 19

The concentrations of extracellular signalling molecules can be very low so amplification may be needed to trigger an appropriate response

Question 20

In cardiac pacemaker cells, stimulation of which receptors cause increase and decrease of heart rate?

Answer 20

Increase: β1 adrenoreceptors are activated by noradrenaline
Decrease: M2 muscarinic receptors are activated by acetylcholine

Question 21

In hepatocytes, how does hormonal stimulation affect glycogen stores?

Answer 21

Insulin binding to receptors stimulates glycogen synthesis

Glucagon binding to receptors stimulates glycogen breakdown

Question 22

Describe phagocytosis

Answer 22

A particle binds to a receptor on the cell membrane
The cell extends pseudopods to invaginate the particle with a membrane zippering mechanism
Internalised phagosomes fuse with lysosomes to form phagolysosomes in which the particle is degraded

Question 23

What is pinocytosis?

Answer 23

The invagination of the plasma membrane to form a lipid vesicle
Permits uptake of impermeable extracellular solutes and retrieval of plasma membrane
Sub divided into fluid phase and receptor mediated endocytosis (RME)

Question 24

Describe receptor mediated endocytosis (RME)

Answer 24

Specific binding of molecules to cell surface receptors permits the selective uptake of substances into the cell

Question 25

Describe the uptake of cholesterol as an example of RME

Answer 25

LDL binds to apoprotein B receptor in clathrin pit on target cell surface Pit invaginates to form coated vesicles Coated vesicles are actively (aka using ATP) uncoated They then fuse with endosomes LDL particle and receptor dissociate Receptor is recycled and returns to plasma membrane Endosome fuse with lysosomes Cholesterol is hydrolysed from the esters and released into the cell

Question 26

Describe the structure of an LDL

Answer 26

Core of fatty acids (esterified cholesterol) | Lipid mono layer of phospholipids, cholesterol and apoprotein B

Question 27

How is cholesterol only absorbed by cells that require it?

Answer 27

The target cells have apoprotein B receptors located in clathrin coated pits which spontaneously form on the cell membrane These pits cover ~2% of the cell surface

Question 28

Why do the LDL receptors and particles dissociate in the endosome?

Answer 28

The pH is lower within the endosome than in the cytoplasm (5.5-6.0) This means the receptor and particle have a lower affinity for each other

Question 29

What is an endosome also known as and why?

Answer 29

A CURL Compartment for the Uncoupling of Receptor and Ligand This is where the receptor and ligand uncouple

Question 30

What are the different ways the LDL receptor can be affected in hypercholesterolaemia?

Answer 30

Non-functioning receptor C-terminal mutation Receptor deficiency

Question 31

What would be the effect of a mutation to the binding site of an LDL receptor?

Answer 31

A mutation in the binding site could change the conformation so the receptor can no longer bind to the LDL so no uptake of LDL therefore LDL receptor os non functional

Question 32

What would be the effect of a mutation to the C-terminal of an LDL receptor?

Answer 32

The receptor interacts with clathrin with it's c terminal domain If there is a deletion of the C-terminal domain, the receptor can't interact with clathrin Therefore the receptors will be spread out across the membrane instead of in the 2% of the membrane where there are clathrin pits

Question 33

How may a receptor deficiency be caused?

Answer 33

By a mutation which prevents expression of the LDL receptor | Eg a start codon deletion

Question 34

Describe the uptake of Fe3+ ions as an example of RME

Answer 34

Two Fe3+ ions bind to apoptransferrin to form transferrin in the circulation Transferrin binds to it's receptor on the cell surface Upon reaching the acidic endosome, the Fe3+ ions release The complex is sorted for recycling back to the plasma membrane where the apoptransferrin dissociates from the receptor

Question 35

Why does the receptor-apoptransferrin complex only dissociate at the membrane?

Answer 35

Affinity at neutral pH is greatly reduced so it is only at the membrane that the apoptransferrin dissociates from the receptor

Question 36

Describe the uptake of occupied insulin receptors

Answer 36

When occupied, the insulin receptors gather over clathrin pits Upon insulin binding, the pit invaginates to form a coated vesicle The vesicle is actively uncoated and fuses with an endosome At the endosome, the insulin-receptor complex remains associated The endosome fuses with a lysosome and both ligand and receptor are degraded

Question 37

What are the three steps of RME that are common to all examples?

Answer 37

Pit invaginates to form coated vesicles Coated vesicles are actively (aka using ATP) uncoated They then fuse with endosomes

Question 38

What is the importance of insulin and it's receptor remaining associated in the endosome?

Answer 38

The mechanism allows for a reduction in the number of receptors on the cell surface This desensitises the cell to constant high circulating insulin

Question 39

What is transcytosis?

Answer 39

When ligands remain attached to their receptors and are transported across the cell Eg maternal immunoglobulins are transferred to the foetus Eg immunoglobulin A is transported from the circulation to bile in the liver

Question 40

What are the modes of RME?

Answer 40

1-Where the receptor is recycled and the ligand degraded 2-Where both the receptor and the ligand are recycled 3-Where both the receptor and the ligand are degraded 4-Where both the receptor and the ligand are transported

Question 41

Give an example and describe the function of a ligand involved in mode 1 of RME

Answer 41

Ligand: LDL Function: metabolic uptake

Question 42

Give an example and describe the function of a ligand involved in mode 2 of RME

Answer 42

Ligand: transferrin Function: Fe3+ uptake

Question 43

Give an example and describe the function of a ligand involved in mode 3 of RME

Answer 43

Ligand: Insulin Function: Metabolic control

Question 43

How do membrane-enveloped viruses and toxins take advantage of RME? Give examples

Answer 43

Once in the endosome, the acidic pH allows the viral membrane to fuse with the endosomal membrane, releasing toxins or viral RNA into the cytoplasm Eg the diphtheria and cholera toxins, both of which bind to the GM1 ganglioside

Question 44

Give an example and describe the function of a ligand involved in mode 4 of RME

Answer 44

Ligand: maternal IgG, IgA Function: transfer of large molecules across a cell