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ESA 1 - ICPP > GPCRs > Flashcards

GPCRs Flashcards

1
Q

How many GPCRs are encoded in the human genome?

A

> 800

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2
Q

Describe the common basic structure of GPCRs.

A
  • Single polypeptide chain
  • 7 transmembrane-spanning regions
  • Extracellular N-terminal
  • Intracellular C-terminal
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3
Q

What is the mode of action of GPCRs?

A
  1. Ligand binds to GPCR - causes R conformational change.
  2. Activated GPCR facilitates GTP for GDP exchange on G alpha subunit of a G protein.
  3. G protein alpha-beta/gamma complex immediately dissociates (into alpha-GTP + free beta/gamma).
  4. Each subunit interacts with effector proteins:
    • second messenger generating enzymes
    • ion channels
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4
Q

What are G proteins?

A
  • Guanine-nucleotide binding protein

- Heterotrimeric: alpha, beta and gamma subunits

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5
Q

What determines the duration of the alpha-GTP and/or beta-gamma interaction with effectors?

A
  • G alpha GTPase activity hydrolyses GTP back to GDP - G protein subunits reform an inactive complex.
  • GTPase activity is poor - up to 5 sec for hydrolysis to occur, allows time for signal transduction.
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6
Q

What would be the consequence of a mutation in G alpha GTPase?

A
  • Mutation that increases activity would decrease response - less time.
  • Mutation that decreases activity would increase response - more time.
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7
Q

What are the 3 different forms of G protein alpha subunits?

A
  1. Gs - activates adenylyl cyclase
  2. Gi - inhibits adenylyl cyclase
  3. Gq - activates phospholipase C
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8
Q

Which second messengers do Gs and Gq activate?

A
  • Gs: catalyses formation of cAMP from ATP by adenylate cyclase.
  • Gq: catalyses formation of IP3 and DAG from PIP2 by phospholipase C.
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9
Q

Which GPCRs are associated with the activities of Gs, Gi and Gq?

A
  • Alpha1 adrenoR - Gq
  • Alpha2 adrenoR - Gi
  • Beta1 adrenoR - Gs
  • Beta2 adrenoR - Gs
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10
Q

Which type of G alpha subunits are associated with cholinergic GPCRs?

A
  • M1 & M3 (muscarinic R): Gq - stimulates phospholipase C
  • M2: Gi - inhibits adenylyl cyclase
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11
Q

How do the cholera and pertussis toxins interfere with G protein function?

A
  • PTx catalyses ADP-ribosylation of Gi - prevents GPCR-G interaction.
  • CTx modifies all Gs containing proteins - unable to hydrolyse GTP - activated for 18-24 hrs before being degraded - very high cyclic AMP concs - cell damage.
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12
Q

What type of effectors are stimulated by GPCR and G protein activation?

A
  1. Enzymes, e.g.
    • adenylyl cyclase (ATP to cAMP)
    • phospholipase C (PIP2 to IP3 + DAG)
  2. Ion channels, e.g.
    • voltage-operated calcium channels
    • G protein-regulated inwardly-rectifying K+ channels (KIRKs)
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13
Q

Describe the diversity of G proteins.

A

Human genome encodes:

  • 20 G alpha
  • 5 G beta
  • 12+ G gamma
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14
Q

Describe the chain of events leading to and following from Gs activation.

A
  1. Agonist binds to GPCR - conformational change.
  2. GPCR mediates GDP replacement by GTP on alpha subunit.
  3. Alpha-GTP dissociates from beta/gamma - activates adenylyl cyclase (AC).
  4. AC converts ATP to cyclic AMP (+2 Pi) - hydrophilic molecule that migrates to cytoplasm.
  5. 4 cAMP bind to 2 regulatory subunits of protein kinase A (PKA).
  6. PKA catalytic subunits are released - phosphorylate a small number of target molecules in cell.
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15
Q

Name some well known endocrine and paracrine agonists that act at Gs-GPCRs.

A

1) Adrenaline (endocrine) - beta adrenoRs
2) Noradrenaline (paracrine) - beta adrenoRs
3) Dopamine (paracrine) - D1 dopamine Rs
4) Histamine (paracrine) - H2 histamine Rs

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16
Q

Name some well known endocrine and paracrine agonists that act at Gi-GPCRs.

A
  1. Adrenaline (endocrine) - alpha2 adrenoRs
  2. Noradrenaline (paracrine) - alpha2 adrenoRs
  3. Dopamine (paracrine) - D2 dopamine Rs
  4. Endogenous opioids (paracrine) - Mu opioid Rs
17
Q

What is signal amplification and why is it used?

A
  • A few ligand molecules can result in a very large cellular response - cascade effect.
  • Body can respond to small changes.
  • E.g. Activation of 1 AC produces many cAMP molecules - can activated many PKA.
18
Q

Describe the chain of events leading to and following from Gq activation.

A
  1. Agonist binds to GPCR - conformational change.
  2. GPCR mediates GDP for GTP exchange on G alpha q subunit - dissociation of alpha-GTP from beta/gamma.
  3. Alpha q subunit activates phospholipase C.
  4. PLC hydrolyses PIP2 into 2 second messengers: diaglycerol (DAG) - remains in PM, and IP3.
    5a. IP3 acts as a ligand for IP3R in ER membrane - calcium release (can increase [calcium] by 5-10 fold).
    5b. DAG activates PKC - phosphorylates own substrates.
19
Q

Name agonists that act at Gq-GPCRs.

A
  • Adrenaline - alpha1 adrenoRs
  • Noradrenaline - alpha1 adrenoRs
  • Acetylcholine - muscarinic ACh Rs 1 & 3
  • Histamine - H1 histamine Rs
20
Q

Describe the GPCR-mediated regulation of inotropy.

A
  1. Adrenaline/noradrenaline bind to beta1 adrenoRs in the ventricles - conformational change.
  2. GDP to GTP exchange on G alpha s - dissociates and activates adenylate cyclase.
  3. AC mediates ATP to cAMP conversion.
  4. 4 cAMP bind to regulatory domains of PKA - dissociate from catalytic domains.
  5. PKA phosphorylates VOOC in membrane - allows calcium entry when membrane depolarises.
  6. Calcium allows myocytes to contract.
21
Q

Describe the GPCR-mediated regulation of vasoconstriction.

A
  1. Sympathetically released NA binds to alpha1 adrenoRs on arterioles.
  2. GPCR mediates GDP for GTP exchange on Gq alpha subunit - dissociates and activates phospholipase C.
  3. PLC mediates hydrolysis of PIP2 into IP3 and DAG.
    4a. IP3 acts as ligand for IP3R in SR of smooth muscle cell - release of calcium into sarcoplasm - increased contractibility.
    4b. DAG stays in PM and activates PKC - phosphorylates own substrates - sustains vasoconstriction.
22
Q

Which ligand, GPCR and effectors are used to cause bronchoconstriction?

A
  • Parasympathetically released ACh
  • Interacts with mAChR on bronchiolar smooth muscle
  • Gq-PLC-IP3/Ca2+ and DAG/PKC pathway
23
Q

Describe the use of GPCRs in the modulation of neurotransmitter release at synapses.

A
  1. Endogenous opioids or analgesics (e.g. Morphine) bind to pre-synaptic mu-opioid GPCRs.
  2. Mediates GDP for GTP exchange on Gi alpha subunit - dissociates from beta/gamma.
  3. Beta/gamma subunits inhibit VOCCs - reduce Ca2+ influx - reduced NT release from pre-synaptic terminal.
24
Q

How does the cholera toxin interfere with G protein function?

A
  • Inhibits GTPase activity of all Gs alpha subunits (through ADP-ribosylation) - unable to hydrolyse GTP to GDP.
  • So G proteins active for 18-24hrs before being degraded - very high cyclic AMP concs.
  • Leads to diarrhoea.
25
Q

How does the pertussis toxin interfere with G protein function?

A
  • ADP-ribosylates the Gi alpha subunit - unable to exchange GDP for GTP - G alpha not activated.

ESA 1 - ICPP (18 decks)

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