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Cell biology > Cell signalling (lectures 14-17) > Flashcards

Cell signalling (lectures 14-17) Flashcards

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1
Q

What is cell signalling?

A

The transfer of information

1) From environment to cells
2) From cell to cell

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2
Q

Why is cell signalling important?

A

Organisms use cell signalling to:

1) Respond to signals from the environment
2) Send signals from cell to cell to coordinate cell behaviour

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3
Q

What aspects of biology does cell signalling affect?

A 
Development 
Nervous system 
Immunology 
Physiology 
Pharmacology 
Cell cycle and DNA repair 
Metabolism
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4
Q

What do signalling pathways do?

A

Convert extracellular signals to cellular response - relay system

There are a huge number of different signalling pathways

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5
Q

What is a simple signalling pathway?

A

1) Signal – extracellular activator of pathway (chemical or physical
2) Reception – detection of signal by receptor protein
3) Response – change in cellular process
• Eg. Gene expression, enzyme activity, cell structure

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6
Q

What are the important components of a signalling pathway?

A

1) Signal – primary messenger / ligand
2) Reception – receptor protein
3) Transduction – transducer proteins
4) Amplification – secondary messengers & signalling cascades
5) Response – response protein
• Transcription factors, enzymes, structural proteins

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7
Q

How can the activity of proteins in a signalling pathway be altered?

A

1) Changing the level of the protein – slow
2) Changing the activity of a fixed amount of protein – fast – by:
• Conformational change or
• Covalent modification eg. Phosphorylation

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8
Q

What are the 5 different types of signalling molecules?

A 
Pheromones 
Hormones 
Cell surface molecules 
Local hormones 
Neurotransmitters
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9
Q

What are gap junctions?

A 
Gap junctions allow small signalling molecules to pass directly from cell to cell 
Channels don’t use energy – diffusion 
• Ions 
• Metabolites 
• NOT macromolecules
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10
Q

What is contact dependent signalling?

A

Not secreted
Signalling molecule on cell surface
Interacts directly with receptor on recipient cell
Important for immune signalling & during development

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11
Q

What is autocrine signalling?

A

‘self’ signalling – cell is able to bind to the signal which it secretes
Other cells of the same type can also bind the signal
Self-stimulating
Important in cancer cells – self-stimulate proliferation & cell growth

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12
Q

What is paracrine signalling

A

Local mediators
Acts on different cell types in close proximity
Important during development

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13
Q

Order the cell signalling methods from shortest distance to longest distance

A 
Gap junction 
Contact dependent 
Autocrine
Paracrine
Endocrine  
Synaptic
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14
Q

Where can receptors be located?

A

On the cell surface

Inside the cell

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15
Q

Hydrophobic signalling molecules

A

Can cross the cell membrane and bind to intracellular receptors

Get into the nucleus and can alter gene expression

Eg. Steroid hormone and NO gas

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16
Q

Hydrophilic signalling molecules

A

Cannot cross the membrane & must bind to cell surface receptors

Signal is transducer into the cell

Eg. Cytokines and neurotransmitters

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17
Q

2 examples of intracellular receptors

A

Nuclear hormone receptors

Nitric oxide receptors

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18
Q

Nuclear hormone receptors

A

Intracellular receptors
Undergo conformational change in response to ligand binding
The receptor-ligand complex regulates transcription of target genes

1) Hormone/ligand binds to receptor
2) Leads to a conformational change
3) Receptor is activated – disconnects from the inhibitor
4) Hormone enters the nucleus
5) Hormone binds to the response element
6) Causes an increase in gene expression

Ligands include cortisol, estradiol, testosterone, vitamin D3, thyroxine & retinoic acid

No receptor no response – a cell can only respond to signals for which it has a receptor

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19
Q

Androgen receptors

A

Intracellular receptor
Androgen steroids (eg. Testosterone) determine male secondary sexual characteristics
In the absence of androgen signalling embryos follow female patterns of development

Androgen insensitivity syndrome
• Is a deficiency of androgen receptors
• Male embryo produces normal levels of testosterone but testosterone is not detected by target cells
• Individuals are genetically male but phenotypically female

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20
Q

Nitric oxide receptors

A

Intracellular receptor
Undergo conformational change in response to ligand binding
Produces a secondary messenger (cGMP)
Nitric oxide involved in vasodilation

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21
Q

What are the 3 classes of cell surface receptors?

A

1) Ion channel coupled - alters membrane permeability to ions
2) G protein coupled (GPCRs) - 7 pass transmembrane receptor - interacts with G proteins in the cell membrane
3) Enzyme coupled - intrinsic enzyme activity or associates with an enzyme to catalyse reaction

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22
Q

What do ion channel coupled receptors do?

A

Also called ligand gated ion channels

Convert chemical signals to electrical signals in nerve synapses

They have a conformational change which allows ions to enter the membrane and depolarise it

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23
Q

How do nicotinic acetylcholine receptors on skeletal muscle cells work?

A
  1. Acetylcholine binds to the receptor
  2. Conformational change
  3. Positive sodium ions flow in
  4. Depolarisation
  5. Calcium released from the SR to the cytosol
  6. Leads to muscle contraction
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24
Q

What is myasthenia gravis?

A
  • Rare long term condition that causes muscle weakness
  • Autoimmune response to nicotinic acetylcholine receptors
  • Auto-antibodies block the receptor
  • Symptoms include drooping eyelids, difficulty moving eyes, walking, speaking clearly & swallowing
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25
Q

What are G-protein coupled receptors (GPCR)?

A

Largest family of cell surface receptors
7 pass transmembrane proteins - pass through the membrane 7 times

Also known as serpentine receptors

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26
Q

What biological processes are GPCRs involved in?

A 
Vision 
Smell 
Neurotransmitters 
Immune regulation 
Autonomic nervous system
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27
Q

What are the 2 types of G-proteins?

A

Trimeric - transduce signals from GPCRs

Monomeric - transduce signals from enzyme linked receptors (e.g.. Ras proteins)

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28
Q

What do G-proteins bind to?

A

GTP or GDP

When bound to GTP they are active
They hydrolyse GTP to GDP to become inactive

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29
Q

What are the 3 heterologous subunits of trimeric G-proteins?

A

Alpha
Beta
Gamma

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30
Q

How does GPCR activation activate G-proteins?

A
  1. Signal molecule comes in & binds to the GPCR
  2. Causes slight conformation in the 7 transmembrane segments
  3. Leads to activation of receptor
  4. Can bind to the trimeric G-protein
  5. Binding causes a conformational change allowing the alpha subunit to bind GTP and releasing GDP
  6. The alpha dissociates and the beta & gamma dissociate together – all still inked to the plasma membrane
  7. Activated subunits can target their downstream effector proteins
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31
Q

How do G-proteins activate other proteins?

A
  1. G-protein transduces signal
  2. Alpha subunit is active & bound to GTP
  3. It moves to bind to its target protein
  4. Leads to a conformational change in the target protein
  5. Target protein is activated
  6. G-protein turns itself off by GTP-hydrolysis (GTP –> GDP)
  7. Once inactive it dissociates from the target protein
  8. Both are now inactive
  9. Alpha subunit re-associates with beta & gamma reforming the trimeric unit
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32
Q

How is GTP converted to GDP?

A

Using a GTPase

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33
Q

What are the 2 key proteins activated by trimeric G-proteins?

A

Adenylyl cyclase

Phospholipase C

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34
Q

What is the second messenger for adenylyl cyclase?

A

cAMP

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35
Q

What are the second messengers for phospholipase C?

A

IP3 and DAG

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36
Q

What does adenylyl cyclase do?

A

It converts ATP to cAMP

By removing 2 phosphate groups and making it into a circle

37
Q

What does cAMP do?

A

cAMP acts as a 2nd messenger in many signalling pathways

cAMP passes information down the signalling pathway by activating cAMP dependent protein kinase (PKA)

38
Q

How does cAMP activate PKA?

A
  • PKA is a dimer (inactive) & binds to its inhibitory proteins
  • cAMP binds to the inhibitory proteins & leads to a conformational change
  • This releases the catalytic domains of PKA
  • They are released & become active
39
Q

What does PKA do?

A

Passes information down the signalling pathway by phosphorylation of other proteins

Covalent modification
Added by kinases
Removed by phosphotases

40
Q

How does the cAMP signalling cascade work?

A
  1. Signal molecule binds to G-protein linked receptor, which activates the G-protein
  2. G-protein turns on adenylyl cyclase, an amplifier enzyme
  3. Adenylyl cyclase converts ATP to cAMP
  4. cAMP activates PKA
  5. PKA phosphorylates other proteins, leading to a cellular response
41
Q

What 3 roles do GTP and ATP have in the cell

A

Nucleic acid synthesis (RNA)
Signal transduction
Carrying energy

42
Q

How does the ‘fight or flight’ response work?

A
  1. Danger or stress
  2. Triggers the peripheral nervous system
  3. Body has a physiological response
  4. Release of adrenaline/epinephrine
  5. Release of energy
43
Q

How does epinephrine cause a release of energy?

A
  1. Epinephrine binds to the GPCR on the surface
  2. G-protein is recruited
  3. Activates alpha subunit – binds to GTP
  4. Activates adenylate cyclase
  5. Coverts ATP to cAMP
  6. Leads to activation of PKA
  7. Activates phosphorylase kinase
  8. Phosphorylase kinase phosphorylates phosphorylase alpha switching it on
  9. Phosphorylase alpha breaks down glycogen stores
  10. PKA also inactivates glycogen synthase by phosphorylation
44
Q

What does phospholipase C do?

A

Cleaves PIP2 to produce IP3 & DAG

Activation of phospholipase C is the same as adenylate cyclase

45
Q

How does the phospholipase C signalling pathway work?

A
  1. It cleaves PIP2 which is linked to the cell membrane
  2. Leads to the 2 signalling molecules
    • IP3 goes into the cytosol
    • DAG remains attached to the membrane
  3. IP3 causes Ca2+ release from the endoplasmic reticulum into the cytosol as it causes the opening of IP3 gated calcium channels
  4. DAG binds to PKC which activates it a bit
  5. DAG & Ca2+ act together to activate PKC to its maximum
  6. PKC regulates many other proteins by phosphorylation
46
Q

Why is calcium a commonly used second messenger?

A

It can bind tightly to proteins inducing a conformational change

47
Q

What does calmodulin do?

A

Many Ca2+ dependent effects are mediated by calmodulin

2 globular domains
• joined by an alpha helix – makes the protein very flexible
• Each calmodulin molecule binds 4 Ca2+ ions to activate it
• The resulting conformational change allows the calmodulin/Ca2+ complex to wrap around and activate target proteins

48
Q

What are enzyme linked receptors?

A

Single span transmembrane proteins

Cytosolic domain has intrinsic enzymatic activity or is associated with an enzyme

Is normally a dimer
• Dimerization leads to activation of enzyme activity in the cell

49
Q

What are receptor tyrosine kinases (RTK)?

A

Receptor tyrosine kinases are the most common type of enzyme linked receptors

They phosphorylate tyrosine

The RTK family includes insulin receptor & many growth factor receptors

50
Q

What do growth factor receptors control?

A

Cell differentiation & proliferation

Cancer is frequently associated with problems in growth factor signalling

51
Q

How do RTK become active?

A
  1. Receptors are inactive in their monomeric form
  2. Signal comes along and binds to receptor
  3. Receptors come together to form a dimer
  4. Formation of dimer leads to activation of kinase activity
  5. Leads to autophosphorylation
52
Q

How do EGF receptors have different mechanisms to RTK?

A

2 dimers come together & cause a conformational change

53
Q

How do insulin receptors have different mechanisms to RTK?

A

Are tetramers

Ligand binding causes realignment of the polypeptide chains activating cross-phosphorylation

54
Q

What do phosphorylated tyrosine residues on the receptor do?

A

Provide docking sites for other signalling proteins

55
Q

What is Ras?

A

Ras is the main signal-transducer protein for growth factors
It is a small monomeric G-protein

56
Q

How are trimeric and monomeric G-proteins different?

A

Trimeric
• Bind directly to receptor
• Receptor activates GDP release
• GTP hydrolysis by intrinsic GTPase activity

Monomeric
• Not directly linked to receptor
• GDP release activates by GEF
• Weak intrinsic GTPase activity - needs GAP to drive GTP hydrolysis

57
Q

What is GEF?

A

Guanine nucleotide exchange factor

58
Q

What is GAP?

A

GTPase activating protein

59
Q

How does RTK activate Ras?

A
  1. Signal is bound to receptor
  2. Becomes a dimer – now activated
  3. Lots of phosphorylation sites
  4. Docking of an adaptor protein (Grb2) to a phosphorylated site
  5. Grb2 can then bring in GEF which can bind to Ras
  6. Ras exchanges GDP for GTP
  7. Ras is now activated
60
Q

What is the Ras-MAPK pathway

A

Ras mitogen activated pathway kinase signalling pathway

61
Q

What are mitogens?

A

Something that makes the cell work

62
Q

How does the activation of Ras change other proteins?

A
  1. Ras is activated
  2. Recruits Raf to the cell membrane
  3. Raf phosphorylates Mek & activates it
  4. Mek phosphorylates Erk & activates it
  5. Erk can change protein activity by phosphorylating other proteins
    • Can phosphorylate transcription factors & alter gene expression
63
Q

What is MAP kkk?

A

Raf

64
Q

What is MAP kk?

A

Mek

65
Q

What is MAP k?

A

Erk

66
Q

How is the Ras signalling pathway involved in cancer?

A

Ras is aproto-oncogene
• Normally functions in a cellular pathway for growth
• Once mutated it drives cancer

Ras mutations are found in 20% of human cancers
• Very high proportion in pancreatic cancers

Most common Ras mutations reduce GTP hydrolysis activity
• GTP stays bound longer & signalling pathway is continually switched on
• Leads to cell proliferation, even in the absence of growth factors such as EGF

67
Q

How can cells response differently to the same signal

A

By using different receptors

By activating different intracellular machinery

68
Q

What are the different types of receptors?

A

Nicotinic – ion channel gated receptors

Muscarinic – G-protein coupled receptors – 7 transmembrane pass proteins

69
Q

How do nitric oxide receptors work?

A
  1. Ach binds to the surface of a GPCR
  2. Increases synthesis of NO
  3. NO diffuses across the membrane into smooth muscle cells
  4. Leads to generation of cGMP
  5. Causes relaxation
  6. Vasodilation
70
Q

What effects does acetylcholine have on pancreatic acinar cells compared to endothelial cells?

A

In pancreatic acinar cells, it leads to activation of a protein kinase – leads to phosphorylation of proteins that cause secretory vesicles to fuse with the membrane to allow secretion of enzymes

In endothelial cells, it leads to the activation of NO synthase

71
Q

How do signalling pathways interact?

A

Different responses need different combinations of signals

Survive
Grow and dive
Differentiate
Die

72
Q

How can signals combine to activate a signalling protein?

A

Phosphorylation of the same molecule

Phosphorylation of separate molecules causing a conformational change allowing the proteins to fit together

73
Q

How do signals combine in glycogen metabolism in muscle cells to alter the activity of GPK?

A

Acetylcholine leads to the release of calcium
• Calcium binds to & activates glycogen phosphoylase kinase (GPK)

Epinephrine induces activation of PKA which also activates the upregulation of GPK

Gets maximal induction of GPK

74
Q

What is the advantage of having overlap between different signalling pathways?

A

Allows fine tuning of response

Different signals can act together to control levels of a 2nd messenger or activity of a signalling protein

75
Q

What is the disadvantage of having overlap between different signalling pathways?

A

Means there is a risk of a signal producing the wrong response

76
Q

What are the 3 types of signalling complexes?

A
  1. Stable - components of the signalling pathway are linked by a scaffold protein
  2. Transient – the signalling complex assembles after the receptor is activated
  3. Transient – modification of plasma phospholipid molecules
77
Q

What does transient mean?

A

Not always there

78
Q

Stable - components of the signalling pathway are linked by a scaffold protein

A

Being organised helps to prevent disasters

Scaffolding protein has inactive proteins docked waiting for activation by a signal

Proteins close together so very efficient

79
Q

Transient – the signalling complex assembles after the receptor is activated

A

Inactive receptor has nothing bound to it

Proteins required are floating around in the cytosol
Signal binds & phosphorylation occurs

Phosphorylation residues indicate where inactive proteins can transiently bind

80
Q

Transient – modification of plasma phospholipid molecules

A

Phosphorylation of phospholipids on the membrane

Recruits separate signalling molecules

Leads to downstream signalling

81
Q

How can signals be switched off?

A

Removal / inactivation of signal

Removal / inactivation of receptor

Inactivation of activated signalling proteins
• GTP hydrolysis
• Phosphorylation / dephosphorylation
• Allosteric

Degradation / removal of second messengers

82
Q

How can a signal be removed?

A

By degradation

By recycling

By sequestration by other proteins
• Hide it away / remove it
• Proteins bind to the signal molecule so it is no longer free to bind to receptors

83
Q

How can receptors be removed?

A

Common mechanism is ligand dependent receptor-mediated endocytosis
• Receptor sequestration
• Receptor down regulation

Removal of receptors allows cells to become adapted to a constant signal – desensitisation

84
Q

Receptor sequestration

A

Temporary

Can remove its signal by taking the receptor away from the cell surface into an endosome
Takes it away from the surface so can no longer respond to the signal
Endosome can fuse back with the membrane

85
Q

Receptor down regulation

A

Permanent

Cell takes receptor into endosome
Endosome fuses with lysosome
Degradation of receptor
Receptor cannot be reassembled

86
Q

How does cholera toxin interfere with G-protein hydrolysis?

A
  1. ADP-ribosylation of Gα prevents hydrolysis of GTP
    • Adds ADP ribose to the alpha subunit
  2. Locks G-protein in an active state
  3. Adenylyl cyclase remains activated
  4. Increase in cAMP leads to loss of Cl- and water into intestinal lumen
  5. Severe watery diarrhoea > dehydration > death
87
Q

How does allosteric inactivation work?

A

By dissociation from activator or association with inhibitor

88
Q

How does viagra work?

A

By inhibiting cGMP phosphodiesterase keeping cGMP levels high

Results in prolonged smooth muscle relaxation

Cell biology (14 decks)

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