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PMCOL 371 > 9 - GPCR > Flashcards

9 - GPCR Flashcards

1
Q

What is the difference between Ionotropic and Metabotropic receptors?

A

Ionotropic = ligand gates ion channel

Metabotropic = G-protein coupled (7TM) receptor (use second messengers)

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2
Q

What is the structure of GPCR’s?

A
  1. Small membrane proteins
  2. Structurally conserved
    • 7 trans-membrane alpha-helices
    • Extracellular loops: ligand binding
    • Intracellular loops: G-protein binding
    • Maintain similar alpha-helix configuration following activation
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3
Q

What is an orphaned receptor?

A

GPCR whose endogenous agonist is unknown

(most are olfactory)

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4
Q

What are G-proteins?

A

Guanine nucleotide (GDP, GTP) binding proteins

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5
Q

G-proteins have intrinsic ____ activity

A

G-proteins have intrinsic GTPase activity

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6
Q

How do G-proteins allow signal transduction?

A

By switching between GTP- or GDP- binding to regulate cell function

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7
Q

What are the two types of G-proteins?

A
  1. Heterotrimeric (alpha, beta-gamma)
         -alpha subunit - most diversity
                   -BINDS GTP OR GDP
												
     - Beta-gamma subunits - function as a unit
  2. Monomeric (Ras superfamily)
          - Homologous to alpha subunit of heterotrimeric
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8
Q

What anchors G-proteins to the membrane? Why?

A

Lipid anchors – allows movement close to the membrane

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9
Q

What are the four main classes of heterotrimeric G-proteins?

A
  1. Galphas - stimulates adenylate cyclase
  2. Galphai
    • includes:
      1. G-alphao - inhibit adenylate cyclase
      2. G-alphat - activate cGMP phosphodiesterase
  3. G-alphaq/11 - activate phospholipase C (PLC - cleaves PIP2 to IP3 and DAG)
  4. G-alpha12/13 - activate Ras (GTPase activating protein) and some tyrosine kinases
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10
Q

Mechanism of G-protein activation

A
  1. Rest
    - G-protein closely associated with GPCR
    - Heterotrimeric
    - High affinity of alpha for GDP
  2. Activation:
    - G-protein binds to GPCR
    - alpha subunit loses GDP
    - alpha has high affinity for GTP
    - G-protein dissociate to alpha + beta-gamma
  3. Termination
    • Free alpha is an intrinsic GTPase
    • Hydrolyze bound-GTP to GDP
    • Heterotrimer reassembles
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11
Q

Addition of ____ prolongs activation

A

Addition of Gpp(NH)p prolongs activation

  • non-hydrolysable analog of GTP
  • Irreversible binding to G-protein - stays dissociated/activated
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12
Q

How is G-protein interaction abolished?

A
  • Pertussis toxin (G-alphai and G-alphao proteins)
    - inactivates G-proteins
    - Places an ADP-ribose onto the GTP-binding site

whooping cough inactivates Galpha i/Galpha o to prevent these signaling pathways

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13
Q

What is direct modulation of GPCR

A
  • G-protein binds directly to ion channel
    - activation of GIRK and KATP channel
    - Inhibit N- and P/Q type VDCC
    - Inhibit Na+ channels
    - Activate Ca++ channels (heart and muscle)
    - Galpha or Gbeta-gamma can both use this pathway

VDCC = voltage-dependent calcium channel

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14
Q

Effects of G-protein binding directly onto the ion channel?

A
  • activation of GIRK and KATP channel
  • Inhibit N- and P/Q type VDCC
  • Inhibit Na+ channels
  • Activate Ca++ channels (heart and muscle)
  • Galpha or Gbeta-gamma can both use this pathway

VDCC = voltage-dependent calcium channel

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15
Q

What is indirect modulation of ion channels by G-proteins?

A
  • G-protein regulate second messengers that alter ion channel activity
    -beta-adrenergic activation of L-type VDCC
    - via cAMP-dependent phosphorylation
  • Muscarinic receptor inhibition of M-current
    -via decrease in PIP2 levels
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16
Q

2 examples of how G-protein regulates second messengers to alter ion channel activity (Indirect modulation)

A
  • beta-adrenergic activation of L-type VDCC
    - via cAMP-dependent phosphorylation
  • Muscarinic receptor inhibition of M-current
    - via decrease in PIP2 levels
17
Q

Provide evidence for direct modulation by G-protein

A
  • Membrane-delimitation
    - Beta-gamma complex remains very closely associated with the membrane
  • Cell-attached mode
    - ACh mimics effect when pipette-applied but not when bath-applied
    - response is restricted to small part of the cell
18
Q

Beta-adrenergic receptors increase ____ current

A

Beta-adrenergic receptors increase L-type VDCC current
- activation of Gs pathway
- Channel phosphorylation

19
Q

Evidence of indirect modulation?

A
  • Cell-attached mode : bath-application mimics effect of agonist
    - Second messengers can diffuse through cytoplasm
    - Can signal to the entire cell from a local input
20
Q

How is rhodopsin (in the retina) indirectly modulated?

A
  • Photon hits rhodopsin and activates tranducin (Galphat)
  • alpha-transducin activates cGMP phosphodiesterase
    - Hydrolyses cGMP on non-inactivating Na+ channe;
  • Na+ channel closes
  • Photoreceptor hyperpolarizes = stops releasing glutamate
  • Loss of transmitter signal activates downstream neuron
21
Q

What is the advantage of indirect modulation?

A
  • Different GPCR’s can produce the same change in an ion channel
    • K+ channels in hippocampal neuron can be modulated by GABAB and/or 5-HT1A receptor
  • Diffusable messengers allow signaling to entire neuron from a local point
  • Control
    - Each GPCR can act at more than one effector to amplify the desired response
    - 5-HT1A receptor in dorsal raphe neurons can activate K+ channels and inhibit VDCCs
  • Direct ion channel modulation localizes and restricts the response to small part of the neuron
22
Q

Advantages of Indirect Modulation:

  • Different GPCR’s can produce the same change in an ion channel
    • K+ channels in hippocampal neuron can be modulated by ______ and/or______ receptor
  • Diffusable messengers allow ________
  • Control
    • Each GPCR can act at more than one effector to _______
      - 5-HT1A receptor in dorsal raphe neurons can activate **_ ** and inhibit **_ **
  • Direct ion channel modulation localizes and restricts the response to small part of the neuron
A
  • Different GPCR’s can produce the same change in an ion channel
    • K+ channels in hippocampal neuron can be modulated by GABAB and/or 5-HT1A receptor
  • Diffusable messengers allow signaling to entire neuron from a local point
  • Control
    • Each GPCR can act at more than one effector to amplify the desired response
      - 5-HT1A receptor in dorsal raphe neurons can activate K+ channels and inhibit VDCCs
  • Direct ion channel modulation localizes and restricts the response to small part of the neuron
23
Q

What is the significance of GPCR’s for neurons?

A

GPCR-mediated effects are slower than those from ionotropic receptors but are longer-lasting

24
Q

What is the implication of having longer lasting effects on neurons (as from GPCR mediated effects)

A
  • changes to neuron behaviour can be induced for an extended period
    • 100s of msec to hours
    • Ionotropic - signaling stops when NT is cleared
    • Metabotropic - signal is prolonged due to delayed onset/offset of second messenger synthesis/catalysis
25
Q

What class of receptors are important for neuromodulation?

A

NPY receptor

26
Q

What are the 5 subtypes of NPY receptors?>

A
  • Y1
  • Y2
  • Y4
  • Y5
  • Y6

PMCOL 371 (18 decks)

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