Receptors

Question 0

How are receptors classified?

Answer 0

Primarily by specificity to a physiological signalling molecule, divided further on the basis of their affinity to a series of antagonists.

Question 1

Define receptor

Answer 1

A molecule that recognises specifically a specific second molecule or family of molecules and in response to binding brings about the regulation of a cellular process.
By definition they are silent at rest, if it operates in absence of a ligand it is an acceptor

Question 2

Give 3 roles of receptors

Answer 2

Signalling via hormones, neurotransmitters and cellular delivery (eg LDLs and transferrin)

Question 3

Define ligand

Answer 3

Any molecule that binds specifically to a receptor site

Question 4

Define agonist

Answer 4

A ligand that produces the activation of a receptor when it binds

Question 5

Define antagonist

Answer 5

A ligand that binds to a receptor without causing activation

Question 6

Why is signal transduction necessary for some signalling molecules?

Answer 6

Hydrophilic signalling molecules cannot pass through the membrane, unlike hydrophobic signalling molecules.

Question 7

How can membrane bound receptors accomplish signal transduction?

Answer 7

Via:

1. Integral ion channels
2. Integral enzyme activity
3. Coupling to effectors via transducing proteins

Question 8

How do membrane bound receptors with integral ion channels work?

Answer 8

Agonist binding results in a conformational change and the opening of a gated channel. The channel then permits the glow of ions down an electrochemical gradient.

Question 9

What’s the structure of the classical family of integral ion channels?

Answer 9

Pentameric subunit structures with four transmembrane domains.

Question 10

Give examples of classical and non-classical integral ion channels

Answer 10

Classical: nAChR, GABA, glycine receptor

Non-classical: Ryanodine receptor, ATP-sensitive K channel, IP3 receptor

Question 11

How do membrane bound receptors with integral enzyme activity work?

Answer 11

Agonist binding to extracellular domains causes a conformational change, which activates integral enzyme activity within the protein structure of the receptor eg tyrosine kinase linked receptors

Question 12

How do tyrosine kinase linked receptors bring about a response within the cell?

Answer 12

They autophosphorylate on receptor binding,
Phosphorylated receptor tyrosine residues are recognised by transducing proteins or directly by enzymes containing phosphotyrosine recognition sites (Src-homology-2 domains).
Effector enzymes are activated allosterically/by tyrosine phosphorylation by the receptor kinase.
This transduces the message into an intracellular chemical event.

Question 13

Give examples of membrane bound receptors with integral enzyme activity

Answer 13

Insulin receptor
Epidermal growth factor receptor
Platelet derived growth factor receptor

Question 14

How do membrane bound receptors with transducing proteins work? (GPCRs)

Answer 14

Seven transmembrane domain receptors (7TMDR) couple to effector molecules via a transducing molecule, a GTP-binding regulating protein (G-protein).
Effectors may be enzymes or ion channels

Question 15

Give examples of G-protein coupled receptors

Answer 15

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

Question 16

What is the full name for a G-protein?

Answer 16

GTP-binding regulatory protein

Question 17

What is integrated signalling?

Answer 17

Where separate G-protein coupled receptors act simultaneously to both stimulate/inhibit the effector.
The two inputs combine to produce a measured effect.

Question 18

What type of ligands bind to intracellular receptors?

Answer 18

Hydrophobic ligands

Question 19

Give examples of hydrophobic ligands

Answer 19

Steroid hormones

Thyroid hormones

Question 20

How do intracellular receptors work?

Answer 20

They are bound to heat shock or chaperone proteins, dissociate when the ligand binds.
They translocate into the nucleus and bind to control regions in DNA, regulating gene expression.

Question 21

Why is the action of intracellular receptors relatively slow?

Answer 21

They are dependent on transcription and translation

Question 22

Give 2 examples of how responses to different receptors can lead to cellular activation/inhibiton

Answer 22

In cardiac pacemaker cells:
NA binding to B1-adrenoceptors increases heart rate, ACh binding to M2-muscarinic receptors decreases heart rate.

In hepatocytes:
Insulin stimulates glycogen synthesis from glucose
Glucagon stimulates glycogen breakdown to glucose

Question 23

Describe the process of phagocytosis

Answer 23

In response to a particle binding to receptors the cell extends pseudopods that permit further receptor interactions and membrane invagination via a ‘membrane zippering’ mechanism.
Internalised phagosomes fuse with lysosomes to form phagolysosomes where the particle material is degraded.

Question 24

Describe the process of pinocytosis

Answer 24

The invagination of the plasma membrane to form a lipid vesicle.
Permits the uptake of impermeable extracellular solutes and retrieval of plasma membrane.

Question 25

What are the 2 forms of pinocytosis?

Answer 25

Fluid-phase

Receptor Mediated Endocyotosis

Question 26

What is Receptor Mediated Endocyotosis (RME)?

Answer 26

The specific binding of molecules to the cell surface permitting the uptake of substances into the cell

Question 27

Describe uptake of cholesterol by receptor mediated endocytosis

Answer 27

LDL receptors are localised in clusters over Clathrin coated pits, these recognise ApoB on the LDL protein
The pit invaginates to form coated vesicles. The vesicles are uncoated (requires ATP) and fuse with endosomes.
The LDL and its receptor dissociate in the low pH (the endosome is the CURL)
Receptor buds off in a vesicle and is recycled to the membrane, the endosomes fuse with lysosomes, cholesterol is hydrolysed from the esters and released into the cell

Question 28

What are endosomes and how do they maintain a low pH?

Answer 28

Endosomes are large smooth vesicles, the low pH (5.5-6) is maintained by an ATP-dependent proton pump.
The endosome is also known as the Compartment for the Uncoupling of the Receptor and Ligand (CURL)

Question 29

Describe the different mutations effecting the LDL receptor in hypercholesteraemia

Answer 29

1. Non-functioning receptor: mutation in LDL binding site prevents uptake
2. Receptor binding normal: deletion in C-terminal domain prevents interaction between receptors and the Clathrin coat, so receptors are distributed across whole surface not concentrated.
3. Receptor deficiency: mutation that prevents expression of LDL receptors

Question 30

Describe the uptake of Fe ions by transferrin by receptor mediated endocytosis

Answer 30

Two Fe ions bind to apotransferrin in circulation to form transferrin, binds to transferring receptors localised in clusters over Clathrin coated pits.
Pit invaginates forming a coated vesicle and is uncoated using ATP. Binds with endosome and Fe ions dissociate at the low pH but apotransferrin remains associated.
Complex is sorted in the CURL for recycling back to membrane where at normal pH the apotransferrin dissociates from receptor.

Question 31

Describe the uptake of occupied insulin receptors by receptor mediated endocytosis

Answer 31

Receptors only congregate over Clathrin coated pits when their agonist is bound (binding induces conformational change that allows recognition by pit).
Pit invaginates and is uncoated using ATP, binds to endosome.
In the endosome insulin remains bound and is targeted to lysosomes for degradation (receptor not recycled).
Means number of receptors on membrane is reduced, desensitising cell to continued high circulating insulin.

Question 32

Explain transcytosis

Answer 32

Transportation of ligands bound to receptors across the cell.

Question 33

Give examples of transcytosis and explain

Answer 33

Transfer of maternal immunoglobulins to the foetus via the placenta.
Transfer of immunoglobulin A from the circulation to bile in the liver.

During transport of IgA the receptor is cleaved, resulting in the release of the immunoglobulin with a bound secretory component derived from the receptor.

Question 34

Give 2 examples of RME where the receptor is recycled and give the fate of the ligands

Answer 34

1. LDLs - ligand is degraded

2. Transferrin - ligand is recycled

Question 35

Give 2 functions of degrading both the receptor and the ligand in RME

Answer 35

Receptor down regulation

Removal of foreign antigens from the circulation

Question 36

Give 3 examples of RME where the ligand is degraded and give the fate of the receptors

Answer 36

1. Transferrin - receptor is recycled
2. Insulin/ epidermal growth factor - receptor is degraded
3. Immune complexes - receptor is degraded

Question 37

What are the 4 modes of receptor mediated endocytosis

Answer 37

1. Receptor recycled, ligand degraded, eg LDLs
2. Receptor recycled, ligand recycled, eg transferrin
3. Receptor degraded, ligand degraded, eg insulin
4. Receptor transported, ligand transported, eg maternal IgG

Question 38

Describe how membrane enveloped viruses and toxins take advantage of receptor mediated endocytosis to gain entry into the cell

Answer 38

They bind to receptors on plasma membrane
Once in the endosome the acidic pH allows the viral membrane to fuse with the endosomal membrane, releasing viral RNA into the cell where it is translated and replicated to form new viral particles.

Question 39

Give examples of toxins that take advantage of RME to enter the cell

Answer 39

Cholera toxin and Diphtheria toxin

Both bind to GM1 Ganglioside