Cell signalling 3 Flashcards
Where are the photoreceptors in a rod cell?
Describe them
Outer segment
- opposite end to light + synaptic region
Discs of photoreceptor membrane containing Rhodopsin GPCR
What does signalling amplification in rod cells allow?
Detection of low light levels for sensitivity
What does adaptation in rod cells allow?
Detection of changes in light levels even in bright light
How do rod cells detect changes in light levels even in bright light?
Many GPCRs are activated
- > closes many ion channels
- > causes cytoplasmic Ca2+ (and Na+) levels to fall
Ca2+ needed by enzymes involved in amplification
Describe the pathway from light hitting the Rhodopsin GPCR to signals being sent to the brain
- 1 Rhodopsin molecule absorbs 1 photon
- Interacts with alpha-transducin -> changes its conformation -> subunit takes up GTP
- Alph subunit activates cGMP phosphodiesterase
- cGMP –> 5’GMP
- Removes cGMP from Na+ ion channels
- Decrease in Na+ inside cell
- Changes charge across membrane
- Interrupts the release of inhibitory neurotransmitters
- Signal passed to brain
How is the signal to the brain from the eye switched off?
i.e. how is the process reversed to resting state?
- All-trans retinal needs to be replaced by a new 11-cis retinal molecule synthesised from VitA
- GTPase converts GTP bound to alpha subunit into GDP
- cGMP is synthesised from GTP by guanylyl cyclase
- stimulated by low Ca2+ levels
How does the absorption of a photon affect Rhodopsin GPCR?
Chromophore retinal is photoisomerised from 11-cis to all-trans retinal by photon absorption
What is a mitogen?
What types of signalling are they?
A chemical substance, usually protein, that induces a cell to begin mitosis
Endocrine or paracrine
Give 3 examples of mitogens
IGF = insulin growth factor
- cell survival + proliferation
PDGF = platelet-derived growth factor
- cell proliferation
NGF = nerve growth factor
- neuron survival
How does receptor tyrosine kinase work?
- Receptor dimerisation
- signal holds 2 tyrosine kinase domains together - Autophosphorylation
- cross-phosphorylate each other -> increases activity of TK domain - Signal protein binding
- small change in conformation allows formation of docking domains for signals
= activates intracellular signalling proteins - Downstream cascade activated
How is receptor tyrosine kinase signalling reversed?
Phosphatase activity
What is the Ras-GAP pathway important in?
Cell proliferation
Describe the Ras protein pathway
- activated RTK has an attached adaptor protein that binds to Ras-GEF
- Activated Gas-GEF activates Ras protein (conformation change -> GDP is replaced by GTP)
- Activated Ras protein interacts w/ next protein in cascade
How is the Gas-GAP pathway reversed?
Promoted by interaction w/ Ras-GAP
GTPase activating protein
What are MAP kinases?
What do they do?
Mitogen-activating kinases
Phosphorylate serine + threonine kinases
Describe the cascade which Ras stimulates
1.Activated Gas protein activates MAP KKK (kinase x3)
2. Activated MAP KKK activates MAP KK using ATP
(2 Pi added)
3. MAP KK activates MAP K using ATP
(2 Pi added)
4. MAP K phosphorylates proteins or TFs using ATP -> ADP
What type of gene are Ras genes?
Oncogenes
- mutated in 30% of cancers
(signals fire constantly -> cell proliferation constantly)
How do RTKs stimulate cell survival?
- Survival signal activates RTK
- Activates PI 3-kinase
- Phosphorylates inositol phospholipid
- Activates protein kinase 1
- Activates Akt via Phosphorylation
(protein kinase 2 also helps to activate Akt)
What does the phosphorylation of inositol phospholipids do?
Creates docking sites for target proteins
-including Akt + PK1
What does AKT inactivating BAD do?
Prevents cell death
Describe how AKT prevents cell death
Akt phosphorylates the BAD protein
- > releases active Bcl2
- > protists cell survival by inhibiting apoptosis
What happens if AKT doesn’t phosphorylate BAD?
BAD would interact w/ Bcl2
–> cell death by apoptosis
What does the activation of mTOR do?
Regulates cell growth
Describe the pathway in which mTOR regulates cell growth
- Growth factor activates RTK
- activates PI 3-kinase
- Activates AKT
- Activates TOR
- Inhibits protein degradation + stimulates protein synthesis
What are the features of TOR?
Nutrient sensing
- if enough amino acids are around, this is relayed to TOR
(as if enough nutrients are mourned cell growth can occur)
What is the importance of the Gas/MAP-kinase pathway?
> Outcome is often cell proliferation (depends on cell type)
Ras neutarlising antibodies can block cell proliferation
Ras gene is mutated in 30% of cancers
Ras + other members of pathway = oncogenes + tumour suppressors
What are the 3 protein conformation ‘switches’ used in cell signalling pathways?
> signalling by protein phosphorylation
signalling by GTP-binding protein
protein-protein interaction (e.g. Ras: GTP -> MAP-KKK)
What does the cross-take between signalling pathways allow?
The integration of diff info for the control of complex cell behaviours
What do activated tyrosine RTKs frequently simulate?
The Ras/MAP-kinase pathway
