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Membranes > Intracellular Signalling > Flashcards

Intracellular Signalling Flashcards

1
Q

What is the purpose of signal transduction?

A

To convert an extracellular signal into a cellular response

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2
Q

What are the 3 main stages of signal transduction?

A
  1. reception
  2. signal transduction
  3. cellular response
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3
Q

What is meant by ‘heirarchy’ in intracellular signalling?

A

It describes how the components of a signal transduction pathway are arranged in a specific order to transmit a signal from the outside of a cell to the inside of the cell

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4
Q

What are the components involved in a hierarchy?

A
  1. first messenger
  2. receptor
  3. G-protein
  4. effector enzyme
  5. second messenger
  6. protein kinase
  7. target protein
  8. cellular response
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5
Q

What is meant by amplification in a signal transduction pathway?

A

The signal transduction pathway amplifies the initial signal

A single first messenger molecule can induce many downstream signalling molecules

This leads to a larger cellular response

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6
Q

How is G-protein activation involved in amplification?

A

A single G-protein molecule can activate many molecules of effector enzyme

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7
Q

How is the effector enzyme involved in amplification?

A

The effector enzyme will catalyse many reactions without being used up

This leads to the production of many molecules of second messenger

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8
Q

How is the protein kinase involved in amplification?

A

The protein kinase will catalyse the phosphorylation of many molecules of protein substrate

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9
Q

What is meant by the specificity of signal transduction pathways?

A

Signal transduction pathways are highly specific

The first messenger may bind to a single receptor to elicit a single response

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10
Q

Can one signalling molecule work on different types of cells?

A

The first messenger must act on the SAME receptor

It can stimulate different responses in different cells due to the differential expression of signalling components

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11
Q

What happens if a signal transduction pathway branches?

A

This leads to more than one cellular response

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12
Q

What is meant by “cross-talk” between two signalling pathways in the same cell?

A

First messengers that bind to different receptors on the same cell may modulate the cellular response

They may activate or inhibit the original signal transduction pathway

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13
Q

What happens if the same first messenger acts on a different type of receptor?

A

This will stimulate a different signal transduction pathway

This leads to a very different cellular response

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14
Q

How does adrenaline act to cause different actions in:

i. muscle and liver
ii. adipose tissue
iii. heart
iv. blood vessels

A

i. stimulates breakdown of glycogen
ii. stimulates fatty acid production
iii. increases the heart rate by stimulating contraction of cardiomyocytes
iv. increases blood pressure by causing relaxation of vascular smooth muscle cells

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15
Q

What are G-proteins and what do they bind?

A

Guanine nucleotide binding proteins

They bind GTP and GDP

(guanosine tri/diphosphate)

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16
Q

What is the role of GTP?

A

It is a high energy molecule that activates G-proteins

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17
Q

What is meant by G-proteins being GTPase enzymes?

A

They catalyse the hydrolysis of GTP to GDP

GDP switches off the G-protein

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18
Q

How are G-proteins anchored to the internal surface of the cell membrane?

A

By lipid tails via prenylation

These tails are either farnesyl or geranylgeranyl groups

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19
Q

What are the 2 major groups of G-proteins?

A
  1. heterotrimeric receptor-associated G-proteins

2. small GTPases

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20
Q

What activates a heterotrimeric receptor associated G-protein?

Why are they heterotrimeric?

A

They are activated by GPCRs

They are heterotrimeric as they contain 3 different subunits: alpha, beta, gamma

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21
Q

How do the subunits vary between different classes of heterotrimeric G-proteins?

Why?

A

They have different alpha subunits but share beta and gamma subunits

The alpha subunits contain the GTPase activity

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22
Q

What is the function and structure of small GTPases?

A

They are monomeric as they only contain 1 subunit

They are involved in cell signalling, cytoskeletal regulation and vesicle trafficking

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23
Q

When are G-proteins active and inactive?

A

They are active when bound to GTP

They are inactive when bound to GDP

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24
Q

What happens when the ligand first messenger binds to its receptor (GPCR)?

A

This induces a conformational change in the receptor allowing the G-protein to bind to the receptor

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25
Q

What happens once the G-protein has bound to the receptor?

A

This stimulates the G-protein to exchange GDP for GTP

This switches it on and allows it to activate the effector enzymes

The G-protein then hydrolyses GTP back to GDP, switching it off

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26
Q

What is the state of the alpha subunit of Gs before the receptor is activated?

A

The alpha subunit of Gs is bound to GDP

It is in the inactive state

Adenyl cyclase is inactive as it has not been activated by a G-protein

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27
Q

What happens when the first messenger binds to the GPCR?

A

The G-protein releases GDP and swaps it for GTP

This switches the G-protein on

The GTP-bound alpha subunit dissociates from the beta and gamma subunits

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28
Q

What happens to the GTP-bound Gs-alpha subunit after it has dissociated?

A

It binds to and activates adenylyl cyclase

This catalyses the conversion of ATP to cAMP

cAMP is the second messenger

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29
Q

What is the role of the GTPase activity of the Gs-alpha subunit?

A

It hydrolyses GTP back to GDP to inactivate the G-protein

The GDP-bound alpha subunit reassociates with the beta and gamma subunits

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30
Q

What will break down cyclic AMP?

A

Phosphodiesterases break down cAMP to AMP

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31
Q

How do different alpha subunits of G-proteins affect different enzymes?

A

Gs - activates adenyl cyclase to increase cAMP

Gi - inhibits adenyl cyclase to reduce cAMP

Gg - activates phospholipase C to increase DAG and IP3

32
Q

How do the actions of Gs and Gi oppose one another?

A

Activating Gs leads to stimulation of adenyl cyclase and increased levels of cAMP

Activating Gi inhibits adenyl cyclase and leads to reduced levels of cAMP

33
Q

How does the cholera toxin affect G-protein activity?

A

It prevents GTPase activity of Gs

GTP remains bound to Gs so that it remains in the active state

34
Q

What is the consequence of the cholera toxin keeping Gs in the active state?

A

It leads to overstimulation of adenyl cyclase and accumulation of cAMP

35
Q

What is the result of accumulation of cAMP in intestinal epithelial cells?

A

Elevated cAMP increases loss of chloride ions through chloride channels

This leads to water being excreted into the intestinal lumen and diarrhoea

36
Q

What causes whooping cough?

A

Bordetella pertussis bacteria in airborne respiratory droplets

37
Q

What is the virulence factor of whooping cough?

A

Pertussis toxin

38
Q

How does the pertussis toxin affect G-proteins?

A

It prevents GDP/GTP exchange by Gi

The Gi protein is locked in the off position and is unable to inhibit adenyl cyclase

39
Q

What is are the physiological effects caused by the pertussis toxin?

A

cAMP accumulates leads to increased insulin secretion and increased sensitivity to histamine

40
Q

What are second messengers?

A

Short-acting intracellular molecules that are rapidly formed as a result of receptor activation

41
Q

What are the 5 common second messengers?

A
  1. cyclic AMP - cAMP
  2. cyclic GMP - cGMP
  3. diacylglycerol - DAG
  4. inositol 1,4,5-triphosphate - IP3
  5. intracellular calcium - Ca2+
42
Q

How are most second messenger molecules formed?

A

Most second messengers are formed from other molecules by effector enzymes

43
Q

What is the difference in the way in which intracellular calcium is formed?

A

It is not formed

It is released into the cytosol from intracellular stores in the ER

44
Q

How is cyclic AMP produced?

A

It is produced from ATP via adenylyl cyclase

45
Q

How is cyclic GMP produced?

A

It is produced from GTP

via guanylyl cyclase

46
Q

How may cGMP be produced using guanylyl cyclase?

A
  1. activation of soluble guanylate cyclase by nitric oxide

2. activation of membrane-bound guanylate cyclase in response to neuropeptides

47
Q

Which phosphodiesterases will break down cAMP only?

A

PDE 4, 7, 8

48
Q

Which phosphodiesterase will break down cGMP only?

A

PDE 5, 6, 9

49
Q

Which phosphodiesterases will break down BOTH cAMP and cGMP?

A

1, 2, 3, 11, 12

50
Q

Why are PDEs important?

What are examples of PDE inhibitors?

A

They reduce the levels of cAMP and cGMP, reducing the response

PDE inhibitors are caffeine and viagra

51
Q

What will activate the Gq activation pathway?

A

Angiotensin II acting on the AT1 receptor

Adrenaline acting of the alpha1-adrenergic receptor

52
Q

What happens to the alpha subunit of Gq before the ligand binds?

A

It is in the inactive state and is bound to GDP

Phospholipase C is inactive as it has not been activated by the G-protein

53
Q

What happens when the ligand binds to the receptor?

A

The receptor associates with Gq

This stimulates the displacement of GDP for GTP and the G-protein is activated

The alpha subunit dissociates from the beta and gamma subunits

54
Q

What will GTP-bound Gq stimulate?

A

It will stimulate membrane-localised phospholipase C

55
Q

What will phospholipase C catalyse once it has been activated?

A

The production of 2 different second messengers from the membrane phospholipid PIP2

  1. diacylglycerol - DAG
  2. inositol-1,4,5-trisphosphate - IP3
56
Q

What happens to IP3 once it has been produced by phospholipase C?

A

It diffuses through the cytosol to the ER

It interacts with Ca2+ channels, leading to the release of stored Ca2+ into the cytosol

57
Q

What happens to DAG once it has been formed by phospholipase C?

A

It remains in the membrane and stimulates protein kinase C

This will phosphorylate target proteins

58
Q

How does intracellular calcium act as a second messenger?

A

It activates various molecules that will modulate cellular function

e.g. calcium dependent kinases

59
Q

What can an increase in intracellular calcium concentration sometimes trigger?

A

The opening of calcium channels in the plasma membrane

This causes even more calcium to enter the cells

60
Q

How is calcium taken back up again?

A

It is taken back up into the ER through a calcium ATPase in the ER membrane

61
Q

What are protein kinases?

A

They are enzymes that facilitate the transfer of a phosphate group from ATP to a specific amino acid residue on a specific protein

62
Q

What amino acid residues can be phosphorylated by protein kinases?

Why?

A
  1. serine
  2. threonine
  3. tyrosine

These residues have side chains containing a hydroxyl group where the phosphate group can be added

63
Q

What is the purpose of phosphorylating proteins?

A

It changes the function of the protein

It may activate or inhibit protein function

64
Q

On which part of the protein can phosphorylation occur and why?

A

It can only occur on intracellular domains of the protein as this is where kinases are found

65
Q

What is a human phosphoprotein?

A

A long protein that has multiple phosphorylation sites

It is phosphorylated by several different kinases

66
Q

What are the 3 main types of protein kinases?

A
  1. serine/threonine kinases
  2. tyrosine kinases
  3. dual-specificity kinases
67
Q

What is an example of a dual-specificity kinase?

A

MAP kinase

They phosphorylate serine, threonine and tyrosine residues

68
Q

What is the role of a phosphatase?

A

They remove phosphate groups from amino acid residues

This opposes the effects of kinases

69
Q

What are the different types of phosphatases?

A
  1. serine/threonine-directed phosphoprotein phosphatases

2. tyrosine-directed phosphotyrosine phosphatases

70
Q

Why are there not as many phosphatases as there are kinases?

A

Phosphatases have a much broader specificity

71
Q

What are the 2 ways in which kinases can modulate protein function?

A
  1. phosphorylation of a protein

This leads to a conformational change that directly alters the function of the protein

  1. phosphorylation of a transcription factor

This activates or inhibits transcription of a gene, and protein expression levels

72
Q

What is the “A pathway” involving adrenaline?

A
  1. adrenaline - first messenger
  2. B1-AR - receptor
  3. Gs
  4. Stimulation of adenyl cyclase
  5. cAMP production
  6. activation of protein kinase A
73
Q

What is the “A pathway” involving acetylcholine?

A
  1. acetylcholine - first messenger
  2. muscarinic M2 - receptor
  3. Gi
  4. Gi inhibits adenyl cyclase
  5. inhibition of cAMP production and protein kinase A
74
Q

What is the “C pathway” in second messenger signalling?

A
  1. angiotensin II
  2. AT1R - receptor
  3. Gq
  4. Gq activates phospholipase C
  5. Phospholipase C activates DAG and IP3
  6. DAG activates protein kinase C

IP3 activates intracellular calcium release

This leads to activation of protein kinase C and Ca/CaM kinase

75
Q

What is the “G pathway” in second messenger signalling?

A
  1. neuropeptide or NO
  2. this directly activates guanylate cyclase
  3. this leads to cGMP production
  4. cGMP activates protein kinase G
76
Q

For which diseases are protein kinase inhibitors being developed for use as therapeutic agents?

A
  1. cancer
  2. cardiovascular disease
  3. HIV/AIDS
  4. rheumatoid arthritis
  5. alzheimer’s
77
Q

Why may protein kinase inhibitors have a use in cancer treatment?

A

Dysregulation of many kinases is directly linked to cancer development

There are changes in protein kinase expression levels in solid tumours

Membranes (5 decks)

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