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Cell signalling (lectures 14-17) Flashcards

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
What are G-protein coupled receptors (GPCR)?
Largest family of cell surface receptors 7 pass transmembrane proteins - pass through the membrane 7 times Also known as serpentine receptors
26
What biological processes are GPCRs involved in?
``` Vision Smell Neurotransmitters Immune regulation Autonomic nervous system ```
27
What are the 2 types of G-proteins?
Trimeric - transduce signals from GPCRs Monomeric - transduce signals from enzyme linked receptors (e.g.. Ras proteins)
28
What do G-proteins bind to?
GTP or GDP When bound to GTP they are active They hydrolyse GTP to GDP to become inactive
29
What are the 3 heterologous subunits of trimeric G-proteins?
Alpha Beta Gamma
30
How does GPCR activation activate G-proteins?
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
31
How do G-proteins activate other proteins?
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
32
How is GTP converted to GDP?
Using a GTPase
33
What are the 2 key proteins activated by trimeric G-proteins?
Adenylyl cyclase | Phospholipase C
34
What is the second messenger for adenylyl cyclase?
cAMP
35
What are the second messengers for phospholipase C?
IP3 and DAG
36
What does adenylyl cyclase do?
It converts ATP to cAMP | By removing 2 phosphate groups and making it into a circle
37
What does cAMP do?
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
How does cAMP activate PKA?
* 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
What does PKA do?
Passes information down the signalling pathway by phosphorylation of other proteins Covalent modification Added by kinases Removed by phosphotases
40
How does the cAMP signalling cascade work?
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
What 3 roles do GTP and ATP have in the cell
Nucleic acid synthesis (RNA) Signal transduction Carrying energy
42
How does the 'fight or flight' response work?
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
How does epinephrine cause a release of energy?
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
What does phospholipase C do?
Cleaves PIP2 to produce IP3 & DAG | Activation of phospholipase C is the same as adenylate cyclase
45
How does the phospholipase C signalling pathway work?
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
Why is calcium a commonly used second messenger?
It can bind tightly to proteins inducing a conformational change
47
What does calmodulin do?
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
What are enzyme linked receptors?
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
What are receptor tyrosine kinases (RTK)?
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
What do growth factor receptors control?
Cell differentiation & proliferation Cancer is frequently associated with problems in growth factor signalling
51
How do RTK become active?
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
How do EGF receptors have different mechanisms to RTK?
2 dimers come together & cause a conformational change
53
How do insulin receptors have different mechanisms to RTK?
Are tetramers | Ligand binding causes realignment of the polypeptide chains activating cross-phosphorylation
54
What do phosphorylated tyrosine residues on the receptor do?
Provide docking sites for other signalling proteins
55
What is Ras?
Ras is the main signal-transducer protein for growth factors It is a small monomeric G-protein
56
How are trimeric and monomeric G-proteins different?
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
What is GEF?
Guanine nucleotide exchange factor
58
What is GAP?
GTPase activating protein
59
How does RTK activate Ras?
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
What is the Ras-MAPK pathway
Ras mitogen activated pathway kinase signalling pathway
61
What are mitogens?
Something that makes the cell work
62
How does the activation of Ras change other proteins?
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
What is MAP kkk?
Raf
64
What is MAP kk?
Mek
65
What is MAP k?
Erk
66
How is the Ras signalling pathway involved in cancer?
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
How can cells response differently to the same signal
By using different receptors By activating different intracellular machinery
68
What are the different types of receptors?
Nicotinic – ion channel gated receptors Muscarinic – G-protein coupled receptors – 7 transmembrane pass proteins
69
How do nitric oxide receptors work?
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
What effects does acetylcholine have on pancreatic acinar cells compared to endothelial cells?
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
How do signalling pathways interact?
Different responses need different combinations of signals Survive Grow and dive Differentiate Die
72
How can signals combine to activate a signalling protein?
Phosphorylation of the same molecule Phosphorylation of separate molecules causing a conformational change allowing the proteins to fit together
73
How do signals combine in glycogen metabolism in muscle cells to alter the activity of GPK?
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
What is the advantage of having overlap between different signalling pathways?
Allows fine tuning of response Different signals can act together to control levels of a 2nd messenger or activity of a signalling protein
75
What is the disadvantage of having overlap between different signalling pathways?
Means there is a risk of a signal producing the wrong response
76
What are the 3 types of signalling complexes?
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
What does transient mean?
Not always there
78
Stable - components of the signalling pathway are linked by a scaffold protein
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
Transient – the signalling complex assembles after the receptor is activated
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
Transient – modification of plasma phospholipid molecules
Phosphorylation of phospholipids on the membrane Recruits separate signalling molecules Leads to downstream signalling
81
How can signals be switched off?
Removal / inactivation of signal Removal / inactivation of receptor Inactivation of activated signalling proteins • GTP hydrolysis • Phosphorylation / dephosphorylation • Allosteric Degradation / removal of second messengers
82
How can a signal be removed?
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
How can receptors be removed?
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
Receptor sequestration
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
Receptor down regulation
Permanent Cell takes receptor into endosome Endosome fuses with lysosome Degradation of receptor Receptor cannot be reassembled
86
How does cholera toxin interfere with G-protein hydrolysis?
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
How does allosteric inactivation work?
By dissociation from activator or association with inhibitor
88
How does viagra work?
By inhibiting cGMP phosphodiesterase keeping cGMP levels high Results in prolonged smooth muscle relaxation

Cell biology (14 decks)

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