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Pharmacology > Receptor Diversity > Flashcards

Receptor Diversity Flashcards

1
Q

The term ‘receptor’ most usually describes a specialised protein which specifically recognises and responds to a single endogenous molecule (or very small group of closely related molecules). Give an example.

A

Adrenoceptors recognise adrenaline and noradrenaline, but do not recognise closely related molecules such as tyrosine, DOPA, dopamine etc.

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2
Q

A receptor only response to one/ very limited number of endogenous ligands. However, it is possible to synthesise chemicals which can also interact with the receptor. How may this occur in nature?

A

One biological organism generates a chemical that can be administered (e.g. through bite/sting) to another species and, via receptor interactions, cause a change in the targeted animal’s physiology (e.g. incapacitation/ paralysis)

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3
Q

How does snake venom incapacitate people who are bitten with it?

A

Contains Ca2+/K+ channel blockers

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4
Q

How can biologically- or chemically- generated ligands act at a receptor?

A
  1. mimic the action of the endogenous ligand (AGONIST)
  2. block the action of the endogenous ligand (ANTAGONIST)
  3. act at a site distinct from the lignd binding (ORTHOSTERIC) site - ALLOSTERIC MODULATOR
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5
Q

How does venom from the green mamba act to incapacitate its victim?

A

Muscarinic receptor antagonist - acts as a negative allosteric modultor

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6
Q

Give an example of:

  1. a ligand-gated ion channel
  2. a kinase-linked receptor
  3. a GPCR
  4. a nuclear receptor
A
  1. nicotinic ACh receptor
  2. EGF receptor
  3. mACh receptor
  4. steroid hormone receptor
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7
Q

With the exception of the insulin receptor, what structure do RTKs take?

A

Single, TM-spanning polypeptides which DIMERIZE on ligand-binding

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8
Q

Following dimerisation, what happens to RTKs?

A

The C-term domains of each monomer phosphorylates the other monomer (AUTOPHOSPHORYLATION) on specific tyrosine residues to form phosphotyrosine (Y-P) docking sites for proteins possessing SH2 domains. This allows RTK to act as a scaffold for intracellular signalling pathways to be assembled and initiated

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9
Q

What residues in RTKs serve as docking sites for proteins possessing SH2 domains?

A

phosphotyrosines

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10
Q

Phosphotyrosines on RTKs serve as docking sites for proteins containing which domains?

A

SH2 domains

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11
Q

What does the presence of phosphotyrosines on RTKs allow for?

A

Docking of proteins containing SH2 domains, which allows the RTK to act as a scaffold for intracellular signalling pathways to be assembled and initiated

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12
Q

How does the insulin receptor differ from most RTKs?

A

It is made up of 4 subunits and comes in a pre-dimerised form

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13
Q

The insulin receptor is ATYPICAL. Give an example of an RTK that is more typical. How is it activated?

A

PDGF receptor. Ligand binds, 2 monomers dimerise, intracellular domains with tyrosine kinase activity are activated and phosphorylate tyrosine residues. Phosphotyrosines act as docking sites for proteins containing SH2 domains.

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14
Q

What percentage of identified genes in the human genome are GPCRs?

A

1-2%

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15
Q

What 4 structural features do all GPCRs share?

A
  1. Single polypeptide chain (300-1200 amino acids in length)
  2. Extracellular N-terminal
  3. Intracellular C-terminal
  4. 7TM-spanning domains
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16
Q

Give some examples of drugs targeted against GPCRs

A

Zyprexa - 5-HT(2A) serotonin receptors - schizophrenia/psychosis
Plavix - P2Y(12) (ADP chemoreceptor) - thrombosis
Fluticasone/Salmeterol - B2-AR - asthama

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17
Q

Which family of GPCRs do adenosine, ATP, opiates, odorants, retinal, catecholamines etc bind do?

A

Family 1A

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18
Q

What family of GPCRs do peptides, cytokines, thrombins etc bind to?

A

Family 1b

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19
Q

What family of GPCRs do glycoproteins and hormones (LH, TSH, FSH) bind to?

A

Family 1c

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20
Q

Which family of GPCRs do calcitonin and secretine bind to?

A

Family 2

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21
Q

What family of GPCRs do glutamate, calcium, GABA(B) and pheromones bind to?

A

Family 3

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22
Q

Which is the largest family of GPCRs?

A

Family A (1) (rhodopsin-like)

23
Q

Where does the ligand bind to the receptor in Family A GPCRs?

A

Specific amino acids within the TM regions contribute to the ligand binding site

24
Q

What are RAMPs?

A

Receptor activity-modifying proteins

25
Q

What do RAMPs do?

A

Selectively interact with SOME family B GPCRs to modify their pharmacological properties, e.g. the calcitonin receptor-like-receptor (CRLR)

26
Q

Give some examples of GPCRs that RAMPs (receptor activity-modifying proteins) bind to and modulate the activity of.

A 
Class B GPCRs for:
secretin
calcitonin
glucaogon
vasoactive intestinal peptide (VIP)
27
Q

How many types of RAMP exist?

A

3

28
Q

RAMPs selectively interact wish some family B GCPRs. Calcitonin receptor-like-receptor (CRLR) is one of these. How does RAMP affect the function of this receptor?

A

Alone, CRLR does not bind any known ligand with high affinity - i.e. it is a non-functional GPCR.
When bound to RAMP1, it binds CGRP (calcitonin gene-related peptide) with HIGH AFFINITY
When bound to RAMP2, it binds ADRENOMEDULLIN with HIGH AFFINITY

29
Q

How does RAMP1 affect CRLR activity?

A

CRLR + RAMP1 binds CGRP (calcitonin gene-related peptide) with high affinity

30
Q

How does RAMP2 affect CRLR activity?

A

CRLR + RAMP2 binds to adrenomedullin with high affinity

31
Q

Expressed alone, calcitonin receptor-like receptor does not bind any known ligand with high affinity. How can it be made to bind to:

1) Calcitonin gene-related peptide (CGRP), and
2) Adrenomedullin

A

1) binding of RAMP1

2) binding of RAMP2

32
Q

What is CRLR?

A

Calcitonin receptor-like receptor

33
Q

What is CGRP?

A

Calcitonin gene-related peptide

34
Q

How can calcitonin receptor-like receptor (CRLR) be made to bind to calcitonin gene-related peptide (CGRP)

A

Through the binding of receptor activity-modifying protein 1 (RAMP1)

35
Q

What is the effect of RAMP1 binding to CRLR?

A

It allows binding of CGRP to the receptor, which stimulates adenylyl cyclase via the G-alpha-s subunit

36
Q

GPCRs were traditionally thought to act as monomers. Over the past decade, however, there has been growing evidence to suggest that Class A GPCRs interact physically and form dimers or higher ordered oligomers. Give some examples of this experimental evidence.

A
  1. High Mw bands seen on SDS-PAGE
  2. Co-immunoprecipitation of epitope-tagged GPCR monomers
  3. Live cell imaging of interactions using FRET/BRET
  4. High-power microscopy techniques to visualise GPCR ‘arrays’
  5. FRAP and TIRF indicate that GPCRs exist in a dynamic equilibrium between monomers and dimers
37
Q

What have FRAP and TIRF indicated about GPCRs?

A

That they exist in an equilibrium between dimeric and monomeric states

38
Q

The crystal structure of which GPCR has recently been obtained? What does this indicate?

A

CXCR4 chemokine receptor - indicates dimeric interfaces

39
Q

Which Family C receptor is a heterodimer?

A

GABA(B) receptor: both GABA(B1)R and GABA(B2)R are required to generate a functional receptor

40
Q

Why is GABA(B) receptor only functional as a heterodimer?

A

GABA(B1)R binds ligand but doesn’t couple to G protein;

GABA(B2)R binds G protein but not ligand (GABA)

41
Q

Each monomer of the heterodimeric GABA(B) receptor fulfils a different function. What does the:

1) B1
2) B2 monomer do?

A

1) B1 contains an ER retention signal and requires co-assembly with a B2 subunit to permit passage to the plasma membrane. B1 binds to GABA (B2 can’t).
2) B2 couples to a G(i/o) protein. B2 may also increase the affinity of B1 for GABA, and B1 may facilitate the coupling of B2 to G(i/o) proteins

42
Q

Which part of the GABA(B) receptor heterodimer is responsible for binding GABA? Which is responsible for coupling to the G(i/o) protein?

A 
GABA(B1)R = responsible for binding GABA
GABA(B2)R = responsible for coupling to the G protein AND moving B1 to the plasma membrane
43
Q

Which family C GPCR functions as a heterodimer?

A

GABA(B) receptor

44
Q

Dimers of which GPCRs have been shown using atomic-force microscopy?

A

Rhodopsin

45
Q

What is the cognate G protein for the GPCR rhodopsin?

A

Gt

46
Q

Which two concepts are gaining increasing acceptance in GPCR pharmacology?

A
  1. pre-coupling of GPCRs with their preferred signalling molecules
  2. GPCR oligomerisation
47
Q

Approximately how many non-sensory GPCRs, where the natural (endogenous) ligand has yet to be identified, await ‘DEORPHANISATION’?

A

Approximately 100

48
Q

Name two recently de-orphanised GPCRs

A
  1. GPR154

2. GPR120

49
Q

Name two recently deorphanised GPCRs. What disorders could each of them be targeted to treat?

A

GPR154: anxiety
GPR120: inflammation, diabetes and obesity

50
Q

What is the ligand for the recently deorphanised receptor GP154?

A

neuropeptide S

51
Q

What is the ligand for the recently deorphanised GPCR GPR120?

A

Omega-3 fatty acids

52
Q

It is becoming increasingly likely that at least a subset of the remaining orphan GPCRs do NOT bind a ligand. How may they fulfil other functions?

A

By hetero-dimerising with other GPCRs to modify their properties

53
Q

What is a receptor?

A

A molecule (usually a protein) inside, or on the surface of, a cell that binds to a specific substance (ligand) and causes a consistent physiological effect in the cell

Pharmacology (13 decks)

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