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PHAR3102 > G-Proteins > Flashcards

G-Proteins Flashcards

1
Q

G-proteins full name

A

guanine nucleotide binding regulatory proteins

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2
Q

What are G-proteins?

A

they are the go-between proteins and act as transducers between receptors and effectors

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3
Q

Two classes of G-proteins have been described

A
  • heterotrimeric G-proteins (large proteins), membrane proteins, consist of alpha, beta and gamma subunits
  • monomeric G-proteins (small proteins), not membrane-associated, but bind GTP and GDP
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4
Q

The structure of heterotrimeric G-protein

A
  • consists of alpha, beta and gamma subunits
  • in the inactive state, 3 subunits are associated together and the alpha subunit binds to GDP (guanosine diphosphate)
  • beta and gamma units are tightly bound with each other
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5
Q

G-proteins - the switch between active and inactive states

A
  • G-proteins are membrane proteins, anchored to the membrane through a fatty acid chain
  • in the inactive state, 3 subunits are associated together and the alpha subunit binds to GDP
  • agonist binding to a receptor causes a conformational change which encourages the receptor to bind to the G-protein complex
  • this coupling causes the GDP bound to the alpha subunit to be exchanged for GTP
  • the G-alpha(GTP) subunit dissociates from the receptor and from the beta and gamma subunits and interacts with the target protein, leading to the generation of second messengers
  • in the meantime, the alpha subunit constitutive GTPase hydrolyses GTP to GDP
  • this hydrolysis process is the turn-off signal that induces G-alpha to disengage from the effectors
  • finally the G-alpha-GDP subunit reunites with the beta and gamma subunits
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6
Q

Summary of G protein activation

A

G-proteins are membrane proteins comprised of 3 subunits: alpha, beta and gamma

  • in the inactive state, 3 subunits are associated together and the alpha subunit binds to GDP (GDP bound G-alpha))
  • agonist-receptor binding causes receptor conformational change, which encourages the receptor to bind to the G-protein complex
  • the receptor-G-protein coupling promotes the exchange of GDP for GTP on the G-alpha subunits
  • the G-alpha(GTP) dissociates from the receptor and from beta and gamma subunits, and interacts with the target protein (e.g. adenylyl cyclase), leading to the generation of second messengers
  • the cycle is completed by the hydrolysis of GTP to GDP by the G-alpha constitutive GTPase, resulting in the re-association of G-alpha(GDP) with the beta and gamma subunits
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7
Q

GPCR signalling cascade

A

receptor (sensory receptors, peptide receptors, hormone receptors, neurotransmitter receptors) –> G-protein –> effector (enzymes - adenylyl cyclase, phospholipase A, phospholipase C; ion channels) –> 2nd messenger (cyclic nucleotides, products of inositol lipids, calcium) –> 2nd effector (enzymes - kinases, phophatases; ion channels)

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8
Q

The main G-proteins subtypes and their functions

  • G-alpha-s
A

G-alpha-s
Associated receptors
- many amine and other receptors (e.g. catecholamines, histamine, serotonin)
Main effectors
- stimulates adenylyl cyclase, causing increased cAMP formation
Notes
- activated by cholera toxin, which blocks GTPase activity, thus preventing inactivation

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9
Q

The main G-proteins subtypes and their functions

  • G-alpha-i
A

G-alpha-i
Associated receptors
- as for G-alpha-s, also opioid, cannabinoid receptors
Main effectors
- inhibits adenylyl cyclase, decreasing cAMP formation
Notes
- blocked by pertussis toxin, which prevents dissociation of alpa-beta-gamma complex

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10
Q

The main G-proteins subtypes and their functions

  • G-alpha-o
A 
G-alpha-o
Associated receptors
- as for G-alpha-s, also opioid, cannabinoid receptors
Main effectors
- limited effects of alpha-subunit (effects mainly due to beta-gamma subunits)
Notes
- blocked by pertussis toxin
- occurs mainly in nervous system
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11
Q

The main G-proteins subtypes and their functions

  • G-alpha-q
A

G-alpha-q
Associated receptors
- amine, peptide and prostanoid receptors
Main effectors
- activates phospholipase C, increasing production of second messengers inositol triphosphate and diacylglycerol

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12
Q

Characteristics of GPCR and G-protein interactions

General

A
  1. Multiple coupling of receptors to different G-protein families
  2. Divergence of signal
  3. Bidirectional control of target enzyme
  4. Convergence of signals
  5. Specificity of receptor-G-protein interactions
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13
Q

Characteristics of GPCR and G-protein interactions

  1. Multiple coupling of receptors to different G-protein families
A
  1. Multiple coupling of receptors to different G-protein families
    e.g. Beta-ARs couple to both Gs (classical) and Gi proteins
    Gs-mediated activation if PKA causes phosphorylation of beta-AR which then switches the receptor coupling to Gi and simulates the mitogen-activated protein (MAP) kinase

see PKA signalling pathway

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14
Q

Characteristics of GPCR and G-protein interactions

  1. Divergence of signal
A
  1. Divergence of signal: Both alpha and beta-gamma subunits are signalling mediators

The specific functions of the beta-gamma complex are not yet known, but it may be involved in:

  • activating potassium channels
  • inhibiting voltage-gated calcium channels
  • activating GPCR kinases
  • activating mitogen-activated protein kinase cascade
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15
Q

Characteristics of GPCR and G-protein interactions

  1. Bidirectional control of a target enzyme
A
  1. Bidirectional control of a target enzyme
    - the heterogeneity of G-proteins allows different receptors to exert opposite effects on a target enzyme (e.g. adenylyl cyclase)
  • in the intestine and bladder, M3 receptor activation causes smooth muscle contraction
  • the ratio of M2:M3 = 70:30
  • M2 receptor doesn’t seem to play a role in the control of smooth muscle activity
  • what is the function of M2 receptor in the intestine and bladder?
    • see diagram
  • M2 receptor inhibits cAMP formation, thus inhibiting cAMP-dependent relaxation of smooth muscle
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16
Q

Characteristics of GPCR and G-protein interactions

  1. Convergence of signals
A
  1. Convergence of signals: different receptors act on the same family of G-proteins

e. g. alpha-2-adrenergic, adenosine A1, muscarinic M2, opioid receptors stimiulate G-alpha-i/o, which leads to:
- inhibition of AC
- activation of K channel (via G-alpha-i and or/ beta-gamma)
- inhibition of calcium channels (via Go)

17
Q

Characteristics of GPCR and G-protein interactions

  1. Specificity of receptor-G protein interactions
A
  1. Specificity of receptor-G-protein interactions
  • Hundreds of GPCRs use a family limited range of G-proteins.
  • How do they get specificity?
  • Studies by antisense oligos-directed against G-alpha, beta, and gamma subunits show that the selectivity of receptor-effector coupling is determined by the specific combination of alpa, beta, and gamma heterotrimers
  • e.g. carbachol acts on M1 muscarinic receptor in basophilic lymphocytes to stimulate PLC via an alpha-q/11-beta-1/4-gamma-4 complex
18
Q

Small GTPases (small G-proteins)

A
  • monomeric G-protein
  • also called the Ras GTPase
  • more than a hundred proteins in this superfamily
  • can loosely be divided into: Ras, Rab, Arf, Ran, Rheb, Rho and Rap families
  • they regulate a wide variety of processes in cells, including growth, cellular differentiation and proliferation, cell survival, angiogenesis, vesicle transport, hypertrophy and cancer etc.
  • G-alpha-12/13 couples to the activation of Rho (see diagram)
19
Q

Diseases associated with G-protein mutations

A
  • Albright hereditary osteodystrophy (AHO) - Gs loss
  • Pseudohypoparathyroidism type 1a - Gs loss
  • Testotoxicosis - Gs gain/loss
  • McCune Albright syndrome - Gs gain (mosaic)
  • Somatotroph adenomas with acromegaly - Gs gain
  • Ovarian and adrenocortical tumours - Gi gain
20
Q

Diseases associated with G-protein mutations

  • Ovarian and adrenocortical tumours
A

Ovarian and adrenocortical tumours

  • G-alpha-i subunit mutations are present in 300% of ovarian sex cord tumours and in adrenocortical tumours
  • activating G-alpha-i mutations result in constitutively activated signal transduction; this may lead to tumourigenesis
21
Q

Diseases associated with G-protein mutations

  • McCune Albright syndrome
A
  • G-alpha-s mutations occur in either Arg201 or Gln227 residues
  • the mutations disrupt the intrinsic GTPase activity, thus the G-alpha-s gets stuck on the “on” position
  • if the mutation affects the skin cells, it causes darker than normal pigment (mosaic)
  • if the mutation affects bone cells, it causes weakness and fractures
  • in hormone-producing cells, the mutation causes excess release of hormones
22
Q

Diseases associated with G-protein mutations

  • Albright hereditary osteodystrophy (AHO)
A

Patients who inherit a heterozygous G-alpha-s mutation develop AHO, a syndrome characterised by one or more of these clinical features:
- short stature, subcutaneous ossifications, centripetal obesity, depressed nasal bridge, and mental or developmental retardation

23
Q

Diseases associated with G-protein mutations

  • Pseudohypoparathyroidism type 1a
A
  • in addition to the AHO phenotype, patients who maternally inherit G-alpha-s mutations also develop resistance to various hormones that stimulate G-alpha-s/cAMP in their target tissues
  • in contrast, patients who paternally inherit G-alpha-s mutations develop only the AHO phenotype
24
Q

Rho-GTPases and cancer

A

Over expression, rearrangement, point mutations or alternative splicing at RHO proteins can cause a variety of different types of tumours/cancers

see Rho signalling pathway

25
Q

Rho GTPases as therapeutic targets in cancer

A

Different strategies to interfere with Rho-GTPase signalling pathway

  • Rho-spatial regulation
  • Rho-GEF interaction inhibition
  • Rho-nucleotide interaction inhibition
  • Effector inhibitors
  • cell migration, cell cycle, apoptosis, gene transcription
26
Q

Common drugs used in large G-protein research

A
  • GTP/GDP analogs: Gpp[NH]p, GTP-gamma-S
  • Pertussis toxin (PTX): catalyses the ADP-ribosylation of the Gi, Go alpha subunits which interferes GDP exchange for GTP
  • Cholera toxin (CTX)-induces ADP-ribosylation of an Arg residue on G-alpha-s-protein and inhibits GTPase activity, resulting in persistent G-protein activation

PHAR3102 (20 decks)

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