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Pharmacology and Toxicology > GPCRs > Flashcards

GPCRs Flashcards

1
Q

What does GPCR stand for?

A

G-protein coupled receptors

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2
Q

What are the major targets of drugs?

A

Enzymes
Transporters
Ion channels
Receptors

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3
Q

What is a receptor?

A

target molecules through which soluble physiological mediators can produce their desired biological effects

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4
Q

What are the types of receptors?

A

GPCR
Ligand gaten ion channels
Enzyme coupled receptors
Nuclear receptors

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5
Q

What is a G-protein coupled receptor?

A

has seven transmembrane domains

Couples to G-proteins to initiate signal transduction

Activated by diverse signals:
photons
hormones
peptides
peptidases
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6
Q

What % of the current drug targets GPCRs

A

50

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7
Q

What does Ranitidine act on?

A

histamine H2 receptors for stomach ulcers

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8
Q

What does Loratidine act on

A

Histamine H1 receptors for allergies

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9
Q

What does Atenolol act on

A

β-adrenoceptors

for hypertension

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10
Q

WHat does Sumatriptan act on?

A

5-HT receptors

for migraines

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11
Q

What does Pilocarpine act on?

A

muscarinic ACh receptors

for glaucoma

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12
Q

What is GPCR Class A?

A

Class A: Rhodopsin-like

Short N terminus
Have extracellular and intracellular loops
Transmembrane domains
C terminal tail

β-adrenoceptors, histamine receptors, dopamine receptors

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13
Q

What is GPCR Class B?

A

Class B: Secretin-like

Large globular N terminus (agonist binding)
Have extracellular and intracellular loops
Transmembrane domains
C terminal tail

secretin receptors, calcitonin receptors, glucagon receptors

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14
Q

What is GPCR Class C?

A

Class C: Metabotropic glutamate/pheromone

Very large N terminus
Have extracellular and intracellular loops
Transmembrane domains
C terminal tail

metabotropic glutamate receptors, GABAB receptors

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15
Q

What is GPCR Class D?

A

Class D: Fungal pheromone

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16
Q

What is GPCR Class E?

A

Class E: cAMP receptors

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17
Q

What is GPCR Class F?

A

Class F: Frizzled/Smoothened

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18
Q

What class do the majority of GPCR drugs target?

A

A

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19
Q

What do GPCRs couple to?

A

heterotrimeric G proteins

20
Q

How are GPCRs activated?

A

agonist binds to receptor so the receptor undergoes a confirmational change
increasing affinity of receptor for heterotrimeric G proteins which when bound exchange GDP for GTP causing the subunits to dissociate and signal to other effectors

21
Q

What happens if a GPCR is activated?

A

Causes signalling events

22
Q

What does IP3 bind to?

A

receptors on endoplasmic reticulum

23
Q

What does the drug salbutamol do?

A

B2-adrenoreceptors
activating GS subunits
increasing cAMP
increasing effect of PKA

24
Q

What does the drug Sumatriptan do?

A

5-HT 1B/D receptors
activate Gi/o subunits
decrease cAMP
decreasing effect of PKA

25
Q

What does the drug Pilocarpine do?

A

M3 muscarinic and ACh receptors
Gq subunits
Increase PKC and Calcium ions

26
Q

What is the desensitisation of GCPRs?

A

prevents activation of them
usually occurs within seconds

Achieved by phosphorylation and/or internalization

Critical to prevent uncontrolled signaling

A reversible ‘switching off’ of the receptors

27
Q

What are the two types of GPCR desensitisation?

A

Homologous

Heterologous

28
Q

What is homologous GPCR desensitisation?

A

Homologous Desensitization: effects are restricted to agonists acting through a specific receptor

29
Q

What is heterologous GPCR desensitisation?

A

Heterologous Desensitization: effects can affect receptors that share a component of the same signaling cascade

30
Q

What is the difference in down regulation vs desensitisation?

A

desensitisation: reduction in the numbers of a functional receptor

Down regulation: is permanent and new receptors must be synthesized i.e., protein synthesis

31
Q

What do beta arrestins do?

A

to regulate G protein-coupled receptor (GPCR) signaling and trafficking.

32
Q

Describe the molecular events that occur after agonist binding that lead to internalization of a GPCR (4 marks)

A
  1. Conformational change
  2. Phosphorylation
  3. Binding of β-arrestins
  4. Recruitment of clathrin
33
Q

G proteins couple to cell-surface receptors to modify the cellular levels of second messenger molecules. Which one of the following molecules is a second messengers?

a) Extracellular-regulated protein kinase (ERK)
b) Protein kinase A
c) 3’-5’-cyclic adenosine monophosphate (cyclic AMP)
d) Gαq
e) Protein kinase C

A

cAMP

34
Q

What promotes internalisation of GPCRs?

A

beta-arrestins

35
Q

What promotes desensitisation of GPCRs?

A

phosphorylation

36
Q

What happens during internalisation of GPCRs?

A

GPCRs internalize to endosomes and then either recycle (recycling) or are degraded (downregulation)

37
Q

What is tolerance? Why?

A

Tolerance is the progressive reduction in the effectiveness of a drug; usually occurring over days or hours

The cellular and molecular mechanisms are not necessarily specified and are often difficult to resolve

Tolerance is a problem in health care industry e.g., morphine

Distinct from the mechanisms involved in desensitization and downregulation

38
Q

What is an enkaphalin?

A
  • Endogenous ligand
  • 5 amino acid peptide (pentapeptide) regulatin regulating nociception
  • Activate µ-opioid receptors
39
Q

What does morphine do?

What is it?

A

Morphine is an analgesic; activates μ-opioid receptors

Biased agonist of those receptors

40
Q

What is a biased agonist?

A

A ‘biased’ agonist differentially activates downstream signaling pathways compared to a ‘standard’ agonist

41
Q

How does biased agonism of morphine affect signalling and traficking?

A

Enkephalins and morphine differentially activate downstream signaling and trafficking pathways

Endogenous agonists such as the enkephalins have a high efficacy for endocytosis

Agonists such as morphine have a low efficacy for endocytosis

42
Q

Enkaphalins activate beta arrestine 1 and 2 what does morphine activate?

A

Beta arrestine 2

43
Q

What happens during the development of tolerance at μ-Opioid Receptors? Using enkaphalins?

A

Normal

GRK desensitization,

β-arrestin

recruitment,

internalization,

resensitization

and recycling

44
Q

What happens during the development of tolerance at μ-Opioid Receptors? Using morphines?

A

Enhanced

PKC phosphorylation.

Impaired internalization,

resensitization

and recycling

processes

45
Q

The development of tolerance to morphine is a major issue for the treatment of pain. Select the best reason why morphine treatment leads to tolerance.

a) morphine promotes degradation of opioid receptors
b) morphine antagonizes opioid receptors
c) morphine promotes a long-lasting desensitization of opioid receptors
d) morphine causes apoptosis
e) morphine activates prevents internalization of opioid receptors

A

C

46
Q

Define tolerance at a G protein-coupled receptor (2 marks)

How does it differ from downregulation? (2 marks).

A

Tolerance is the progressive reduction in the effectiveness of a drug (1 mark), usually occurring over days or hours (1 mark)

Down-regulation is the reduction in the number of functional receptors (1 mark), whereas tolerance does not involve a change in receptor number (1 mark)

Pharmacology and Toxicology (7 decks)

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