ICPP 9 - Receptors & Ligands

Question 1

Describe the process of paracrine, endocrine and synaptic signalling by secreted molecules.

Answer 1

Paracrine = local chemical mediator released into interstitial space to work on close proximity adjacent cells.

Endocrine = hormone released into blood stream and circulates around body to have effect on long distance targets.

Synaptic = NT released into synaptic cleft to bind to receptors on post-synaptic membrane/target cell.

Question 2

What are the signalling molecules used in paracrine, endocrine and synaptic signalling?
Why does this classification no longer hold true?

Answer 2

• Paracrine = local chemical mediators. Endocrine = Hormones. Synaptic = NT’s.
• There can be overlap between categories, e.g.: NT’s can be hormones.

Question 3

What type of ligands bind to EC receptors?

What type of ligands bind to IC receptors?

Answer 3

• Hydrophilic

- Hydrophobic (as they can pass hydrophobic bilayer)

Question 4

What is the definition of a receptor?

Answer 4

A molecule that recognises a second molecule (ligand) which regulates a cellular process in response to binding In the unbound state, a receptor is functionally silent.

Question 5

What is a ligand and the 2 classes a ligand can be?

Answer 5

• A ligand is a molecule that binds specifically to a receptor site.
• Agonist if it produces activation of a receptor.
• Antagonist if it binds without causing activation, opposing the effects of agonist binding.

Question 6

Is the affinity for ligands for receptor sites higher or lower than substrates to enzyme binding sites and why?

Answer 6

Receptor binding sites as these ligands are diluted before reaching their target (typically nanomolar to picomolar Km).

Question 7

How is a receptor classified and sub-classified?

Answer 7

• Classifieds according to the agonist that binds to it
• Sub-classified by the affinity of a series of antagonists

E.g.: mAChR is classified by muscarine binding, and sub-classified (M1-M5) by the different antagonists that bind.

Question 8

What is the difference between a receptor and acceptor?

Answer 8

Receptor = silent at rest, binding stimulates biological response.

Acceptor = operate in absence of ligand, ligand binding alone wont produce response.

Question 9

What are the 4 different receptor types/mechanisms by which receptors transduce a signal from a ligand? (list from fastest to slowest)

Answer 9

1) Membrane bound receptor w/integral ion channels (ionotropic receptors)
2) Membrane-bound receptors w/integral enzyme activity
3) Membrane-bound receptors coupled to effectors through transducing proteins (GPCR’s)
4) Intracellular receptors

Question 10

What is the “model” ligand-gated ion channel receptor (ionotropic receptor)? Describe its structure.
Do all of these channels have this structure?

Answer 10

• The nAChR. It is a pentameric complex (5 subunits coming together to form an integral ion channel). Gate is opened upon binding of ACh, and negatively charged AA’s in pore select for cations to move through, causing DP. The binding domain is in the N-terminus region.
• No, other ionotropic receptors have different structures.

Question 11

Describe the structure of membrane-bound receptors with integral enzyme activity and give examples.

Answer 11

• Has an N-terminus which is the binding domain and C-terminus which is the catalytic domain linked in a dimeric form.
• ANP receptor (linked to GC) and growth factor receptors, e.g.: EGF and PDGF (linked to tyrosine kinase)

Question 12

How does signalling via tyrosine kinase receptors work?

Answer 12

• Autophosphorylation of receptors, then either to activation of enzyme or activation of transducer.

Question 13

Describe the process of GPCR/7TMD receptor activation and give 2 examples of GPCR’s.
Where does the ligand bind on GPCR’s?

Answer 13

• Ligand binds to receptor binding site, GDP replaced with GTP, G-protein sub-units dissociate which activate 2nd messengers causing intracellular effects.
• Examples = mAChR (M1-M5) & B-adrenoreceptors
• Normally in a cleft of the 7TM domains but also sometimes in the N-terminus

Question 14

Describe how binding of a ligand activated intracellular receptors, and how they achieve their effects.

Answer 14

At rest, intracellular receptors prevent binding to DNA by inhibitory protein complex, binding of ligand causes conformational change which reveals DNA binding site. Receptor will then bind to DNA to affect transcription.

Question 15

Which receptor type can undergo significant amplification of signal upon ligand binding?

Answer 15

GPCR - as they cause a cascade of reactions which activate enzymes at multiple steps.