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phar2005 term 1 > Receptor Structure > Flashcards

Receptor Structure Flashcards

1
Q

What are the four structurally distinct receptor families?

A
  1. Ligand-gated ion channels (LGICs)
  2. G-protein coupled receptors (GPCRs)
  3. Kinase-linked and related receptors
  4. Nuclear receptors
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2
Q

Please give an example for each of the four families.

A

LGICs - nAChR
GPCRs - mAChR
Kinase-linked - insulin receptor
Nuclear - oestrogen receptor

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3
Q

Describe the structure of LGICs.

A

LGICs are:

  • multi-subunit (oligomeric) as either pentameric, tetrameric or trimeric
  • transmembrane proteins
  • contain an integrated ion channel
  • are either excitatory (e.g. Na+ channel) or inhibitory (Cl- channel)
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4
Q

Distinguish between the excitatory and inhibitory LGICs

A

Excitatory <===> receptors for ACh, 5-HT, Glu and ATP

Inhibitory <===> Receptors for GABA and Gly

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5
Q

Distinguish between the pentameric, tetrameric and trimeric LGICs

A

Penta <===> nAChR, GABA(A)R, GlyR, 5-HT(3)R

Tetra <===> GluR

Trimeric <===> P2X

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6
Q

List some examples of neurotransmitter LGIC receptors.

A 
ACh <===> nAChR
5-HT <==> 5-HT(3)R
GABA <==> GABA(A)R
Gly <==> GlyR
Glu <==> GluR
ATP <==> P2X
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7
Q

What are the subtypes and subunits of nAChR?

A

Subtypes: muscle, neuronal

Subunits:
muscle <==> alpha(1), beta(1), gamma, delta, epsilon

neuronal <==> alpha(2) - alpha(10), beta(2) - beta(4)

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8
Q

What are the subunits of GABA(A)R?

A 
alpha(1) - alpha(6)
beta(1) - beta(3)
gamma(1) - gamma(3)
delta
epsilon
theta
pi
rho(1) - rho(3)
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9
Q

What are the subtypes and subunits of GluR?

A

subtypes: AMPA, Kainate, NMDA

subunits:
AMPA <==> GluA1 - A4
Kainate <==> GluK1 - K5
NMDA <==> GluN1, N2A - 2D, N3A - 3B

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10
Q

What are the subunits of

5-HT(3)R?

A

5-HT(3)A - 5-HT(3)E

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11
Q

What are the subunits of

ATP (P2X) R?

A

P2X(1) - P2X(7)

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12
Q

Describe the structure and nAChR.

A
  • expressed at the NMJ and within the CNS and PNS
  • also expressed in high density in the electric organ of the marine ray ‘Torpedo’ (alpha(2)-beta-gamma-delta)
  • three dimensional structure of Torpedo nAChR obtained through cryo-electron microscopy
  • has two conformations: open and closed
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13
Q

State five subtypes of GPCRs.

A
  • Neurotransmitters
  • Neuropeptides
  • Peptide hormones
  • Glycoprotein hormones
  • Odorants
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14
Q

What are G-proteins?

A

Heterotrimeric proteins composed of alpha, beta, and gamma subtypes that catalyze the interconversion of the GTP and GDP

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15
Q

Describe the structure of GPCRs.

A
  • Extracellular N-terminus
  • Intracellular C-terminus
  • 7 alpha-helical transmembrane domains
  • several GPCRs exist as dimers (either homo- or hetero-dimers)
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16
Q

Give an example for a GPCR that exists as a dimer

A

GABA(B)R1 fails to form a functional cell-surface receptor unless as a dimer with GABA(B)R2

17
Q

What was the first GPCR structure determined?

A

Rhodopsin, a light-sensing protein involved in the visual system

18
Q

What was the first ligand-binding GPCR structure determined?

A

Beta(2) - adrenoceptor structure determined in 2007.

Beta(2) - adrenoceptor coupled to a cytoplasmic heterotrimeric G-protein structure determined in 2011.

19
Q

Describe how GPCRs mediate intracellular signalling.

A
  • GPCRs mediate intracellular signalling via interaction with intracellular G-proteins.
  • Activation of GPCRs leads to the release of GTP-bound alpha subunits
  • These then diffuse away and activate various enzymes, such as adenylate cyclase and phospholipase C
  • This modulate the synthesis of second messengers of cAMP and IP(3).
  • G-proteins can also act by modulating the function of ion channels.
20
Q

List the different subtypes of GPCRs and provide an example for each.

A

Muscarinic AChRs <==> mAChRM(1) - mAChRM(5)

Metabotropic GluRs <==> mGluR(1) - mGluR(7)

5-HT receptors <==> 5-HT(1)R, 5-HT(2)R, 5-HT(4)R - 5HT(7)R
(note that 5-HT(3)R is a LGIC)

GABA receptors <==> GABA(B)R1, GABA(B)R2

Dopamine receptors <==> D1A, D1B, D2 - D5

Adrenergic receptors <==> alpha(1), alpha(2)A - alpha(2)C, beta(1) - beta(3)

21
Q

Describe the structure of Kinase-linked and related receptors.

A

N-terminus — Ligand binding domain — [single transmembrane domain] — intracellular catalytic domain — C-terminus

22
Q

What form of substrates bind to Kinase-linked and related receptors? Provide some examples.

A

They act as receptors for a wide range of signalling molecules, all of which are peptides.

Examples include:

  • peptide hormones (e.g. insulin)
  • growth factors (e.g. epidermal growth factor (EGF))
  • cytokines
23
Q

How are Kinase-linked and related receptors sub-divided? Provide some examples.

A

Based on signalling / catalytic activity. For example:

  • tyrosine kinase receptors
  • tyrosine kinase-linked receptors
  • serine/threonine kinase receptors
  • guanylate cyclase receptors
24
Q

What happens if a receptor lacks an intrinsic catalytic activity?

A

It typically binds to cytosolic kinases and activate them after receptor activation. A common mechanism of action is for ligand binding to cause receptor dimerisation.

In receptors with intrinsic tyrosine kinase activity, this can result in auto-phosphorylation of tyrosine residues, which in turn can lead to binding of a group of intracellular proteins called SH2-domain proteins.

25
Q

Describe the structure and function of Nuclear (intracellular) receptors

A

N-terminus — DNA binding domain — Ligand-binding domain — C-terminus

Nuclear receptors are soluble receptors, rather than transmembrane receptors.

Nuclear receptors regulate gene transcription.

26
Q

What is the effect of a ligand binding to a nuclear receptor?

A

Induces a conformational change which promotes dimerisation.

The dimeric, ligand-bound receptor is able to act as a transcription factor by binding to specific regions of genomic DNA, promoting binding of RNA polymerase and thereby leading to gene transcription (of genes linked to hormone-responsive elements).

27
Q

State the time periods relating to the effect of each of the four receptor families.

A

LGICs <==> fast (milliseconds)

GPCRs <==> slower (seconds)

Kinase-linked <==> even slower (hours)

Nuclear <==> slow (hours, sometimes days)

phar2005 term 1 (10 decks)

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