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Pharmacology 3 > L4: Receptor Superfamilies > Flashcards

L4: Receptor Superfamilies Flashcards

1
Q

What are the possible drug targets?

A
  • Receptors,
  • ion channels,
  • enzymes,
  • transporters
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2
Q

What are the possible Ligand-Receptor interactions?

A

1) Ligand binds to cell surface receptors (rapid)
water soluble molecules, short half-life, which modulate:
- cAMP, phosphtidylinositides
- excitability
- a kinase/phosphatase cascade

2) Ligand binds to intracellular receptors (slow)
lipophilic molecules that diffuse through the plasma membrane, e.g. steroid and thyroid hormones

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3
Q

Name receptor superfamilies

A
  • ionotropic (ligand gated ion channels)
  • metabotropic (G-protein coupled receptors)
  • kinase linked receptors
  • nuclear / intracellular receptors
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4
Q

Describe ionotropic (ligand gated ion channels) receptors (activation speed, position within the membrane, example)

A
  • very quick, millisecond activation
  • membrane spanning
  • hyperpolarization (less likely to activate) / depolarization (activates quicker)
  • e.g. nicotinic AChR
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5
Q

What’s the speed of ionotropic receptors activation?

A

very quick, millisecond

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6
Q

Describe metabotropic (GPCRs) receptors (activation speed, position within the membrane, function, example)

A
  • quick, but not as ionotropic, activation in seconds
  • membrane spanning
  • second messengers / protein phosphorylation
  • e.g. muscarinic AChR
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7
Q

What’s the speed of metabotropic receptors activation?

A

quick, but not as ionotropic, activation in seconds

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8
Q

Describe kinase linked receptors (activation speed, position within the membrane, mechanism, example)

A
  • slow, activation in hours
  • membrane spanning
  • protein phosphorylation => changes in gene transcription and protein synthesis
  • e.g. insulin, cytokines
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9
Q

What’s the speed of kinase-linked receptors activation?

A

Slow, activation in hours

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10
Q

Describe nuclear / intracellular receptors (solubility, activation speed, position, mechanism, example)

A
  • intracellular, ligand must pass through cell membrane (must be lipophilic)
  • transduction of effect takes hours
  • ligand-receptor => DNA => changes in gene transcription and protein synthesis
  • e.g. steroid hormones, vitamin D
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11
Q

What’s the speed of nuclear / intracellular receptors activation?

A

Transduction of effect takes hours

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12
Q

What are the possible ligands of nuclear / intracellular receptors?

A
  • steroid hormones (oestrogen (oestrogen receptor); testosterone (androgen receptor); cortisol (glucocorticoid receptor); aldosterone (mineralcorticoid receptor); progesterone (progesterone receptor))
  • thyroid hormone
  • vitamin D
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13
Q

What is the structure of nuclear receptors?

A
  • regulatory domain (Activation Function-1; regulates R activity)
  • DNA binding domain
  • Hinge (shape of receptor)
  • ligand binding domain (Activation Function-2)
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14
Q

Describe regulatory domain of nuclear receptors (variability, structure, function)

A
  • very variable, both sequence and length
  • contains transcriptional activation function, AF-1
  • AF-1 binds elements (co-activator or co-repressor proteins) that modify the ability of the receptor to increase or decrease gene transcription via DNA binding domain
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15
Q

How variable or conserved is regulatory domain of nuclear receptors?

A

Very variable, both sequence and length

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16
Q

Describe DNA binding domain of nuclear receptors (variability, action, structure)

A
  • highly conserved
  • localises receptor on DNA and involved in receptor dimerisation
  • contains 2 Zn2+ fingers that wrap around the DNA helix
  • 4 cysteines in each finger chelate one Zn2+ ion
  • proximal zinc finger (P box; determines specificity) and distal (D box)
17
Q

How variable or conserved is DNA binding domain of nuclear receptors?

A

highly conserved

18
Q

What’s the mechanism of action of DNA binding domain of nuclear receptors?

A

localises receptor on DNA and involved in receptor dimerisation

19
Q

What’s the structure of DNA binding domain of nuclear receptors?

A
  • contains 2 Zn2+ fingers that wrap around the DNA helix
  • 4 cysteines in each finger chelate one Zn2+ ion
  • proximal zinc finger (P box; determines specificity) and distal (D box)
20
Q

What are response elements in nuclear receptors context?

A
  • Nuclear receptors regulate transcription by binding to DNA-response elements using their conserved DNA-binding domains.
  • These response elements contain conserved hexameric sequences that can be arranged in various bipartite configurations, including inverted and direct repeats.
  • Response elements show palindrome sequences.
21
Q

Describe hinge domain of nuclear receptors

A
  • less well conserved
  • flexible, links the ligand-binding domain to the DNA binding domain - allows tertiary structure of protein
  • role in nuclear localisation
22
Q

How variable or conserved is hinge domain of nuclear receptors?

A

less well conserved

23
Q

What is the role of hinge domain of nuclear receptors?

A
  • flexible, links the ligand-binding domain to the DNA binding domain - allows tertiary structure of protein
  • role in nuclear localisation
24
Q

Describe ligand binding domain of nuclear receptors (variability, function, role)

A
  • variable sequence
  • involved in nuclear localisation and dimerisation
  • important role in regulation of ligand dependent transcriptional activation through AF-2 sequence in carboxy terminus
  • agonist ligands stabilise the receptor conformation that is optimal for efficient interaction with co-activators, with AF-2 domain exposed
  • antagonists have bulky side chains that hinder H12 from aligning in the agonist conformation.
25
Q

What is the role of ligand binding domain of nuclear receptors?

A

important role in regulation of ligand dependent transcriptional activation through AF-2 sequence in carboxy terminus

26
Q

How variable or conserved is ligand binding domain of nuclear receptors?

A

Variable sequence

27
Q

What is the function of co-activators in regulatory domain of nuclear receptors?

A
  • recruited by DNA bound, ligand bound receptor
    agonist ligands stabilise the receptor in a conformation that is optimal for efficient interaction with co-activators and facilitates transcriptional activation
28
Q

What is the function of co-repressors in regulatory domain of nuclear receptors?

A
  • recruited by DNA bound unliganded receptor OR antagonist bound receptor - help repress transcription
29
Q

How do nuclear receptors alter transcription?

A

receptors cause ‘remodeling’ of chromatin to allow transcription factor access into the promoter region

30
Q

What are the possible modifications of chromatin remodelling?

A

chromatin remodelling complexes include proteins with ability to modify histones:
- histone acetylation correlates with increased transcription
- conversely, deacetylation correlates with increased repression
- other modifications include methylation, sumoylation, phosphorylation

31
Q

What are the two mechanisms of nuclear receptors action? Describe them

A
  • Type I. Receptors in inactive state bound to chaperones, when ligand binds, receptor dimerises and then binds to DNA, e.g. steroid receptors
  • Type II. Receptors already dimerised on DNA in inactive state before ligand binds, e.g. Retinoid X receptor (RXR), Liver X receptor (LXR)
32
Q

Describe class I of Nuclear Receptors (affinity, location, chemical knowledge)

A
  • endocrine ligands
  • high affinity
  • mainly homodimers
  • cytosolic location
33
Q

Describe class II of Nuclear Receptors. (affinity, location, chemical knowledge)

A
  • lipid ligands
  • low affinity
  • mainy heterodimer with RXR
  • nuclear location
34
Q

What are selective receptor modulators?

A

example: selective estrogen receptor modulators, mimic estrogen in some tissues, antagonises it in others
e.g. raloxifene: agonist in bone, on lipid profile (decrease LDL); antagonist on breast, in endometrium

Pharmacology 3 (21 decks)

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