Cell signalling 3 Flashcards
rod photoreceptor provides
monochrome vision in low light
Where is the rhodopsin GPCR
in membrane discs in the outer segment
receptors at the back of the eye with light coming in the opposite end
Light signalling to the brain process
Light strikes GPCR receptors on the inner membrane, rhodopsin absorbs a photon
Receptor interacts with alpha transducin, activated and changes conformation and takes up GTP, releases GDP
Interacts with target protein cGMP phosphodiesterase, activated, which hydrolyses cGMP to 5’GMP
cGMP usually holds ion channels open, so when when it is removed the channels close- stops Na+ entering cell (across plasma membrane)
1mv membrane potential change, inhibitory nt not released so signals are transmitted to the brain
Reversion to the resting state- switching off the signal: Rhodopsin GPCR
Chromophore retinal in photoisomerised from 11-cis to all-trans by absorbing a photon and needs to be replaced by a new 11-cis retinal
This is synthesised from vitamin A
Reversion to the resting state: alpha transducin
Self inactivating G protein alpha subunit
GTPase activity hydrolyses GTP to GDP
Reversion to the resting state: cGMP
Synthesis of cGMP from GTP by guanyl cyclase
Stimulated by low ca levels
Signal amplification allows
detection of low light levels for sensitivity
Adaption allows
detection of changes in light levels even in bright light
Due to many GPCRs being activated, closing many ion channels and ca cytoplasmic levels fall (along with Na)
Ca is needed to activate enzymes involved in amplification
Receptor tyrosine kinase
Has intrinsic enzyme activity (unlike GPCR)- enzyme it contains is tyrosine kinase
Incl mitogens
Mitogens
Meditate local/short range communication
autocrine/paracrine signalling
Act as signals for receptor tyrosinase kinase signalling
Act at low conc and high specificity for receptors
Examples of mitogens
Insulin like growth factor- cell survival and proliferation
Platelet- derived growth factor- cell proliferation
Nerve growth factor- neuron survival
Tyrosinase kinase receptor dimerisation
The inactive RTKs are monomeric- have to come together and function as a pair
Happens by the signal binding- holds the 2 copies together
When brought together the kinase activity is stimulated
Autophosphorylation
Tyrosine kinases autophosphorylate one another/ cross phosphorylate
Addition of phospahtes incr activity of Tyrosine Kinases
Additional tyrosine residues in the receptor get phosphorylated
Signal protein binding
Change in conformation around each phosphate allows docking of signalling proteins that initiate the next step of the signalling cascade
Become activated intracellular signalling proteins
Signalling rapidly reversed by
phosphatase activity
Adaption occurs due to
receptor internalisation and degradation
Ras activation
Have activated RTK
Interaction of specific domain with adaptor protein
Adaptor protein interacts in turn with Ras-GEF which activates the Ras protein
Ras protein releases GDP, takes up GTP . Change in conformation means it can interact with the next protein and allow onward transmission of signal
Reversal promoted by
interaction with Ras-GAP
GTPase activating protein (activates GTPase activity in Ras)
Ras
monomeric GTPase (same as alpha subunit of GPCR)
Ras stimulates
serine/ threonine kinase cascade
How does activated RAs stimulate a cascade
interact with MAP kinases and activate them
What does activation of MAP kinases cause
Promotes cell proliferation
Leads to phosphorylation of protein targets to cause changes in protein activity and phosphoryation of TFs to cause changes in gene expression
All of the proteins are coded for by
oncogenes
RTKs stimulate cell survival through
PI3-Kinase
How does activation of PI3-kinase work and what does it trigger
PI3-kinase docks to activated RTK and becomes activated
Phosphorylates inositol phospholipids.
These (inositol phospholipids) act as a docking site for target proteins
eg protein kinase 1 and Akt
Protein kinase one phosphorylates Akt and protein kinase 2 interacts, resulting in the signal being relayed onward by activated Akt
Akt inactivates
BAD protein by phosphorylation
What does inactivation of BAD do
Prevents BAD interacting with Bcl2 like usual, to allow cell death by apoptosis
Phosphorylation of BAD releases active Bcl2 nad inactive bad, promotion of cell survival by inhibition of apoptosis
Activated Akt can also activate
Tor
Activation of mTOR
regulates cell growth
inhibition of protein degradation
Stimulation of protein synthesis
Leads to cell growth
Importance of Ras/MAP-kinase pathway
outcome depends on cell type, often promotes cell proliferation
Ras neutralising antibodies can block cell proliferation
Ras gene is mutated in 30% of all human cancers
Ras and other members of the pathway are oncogenes and tumour suppressors
Protein conformation switches
Used in cell signalling pathways
Protein kinase phosphorylates protein to activate, then protein phosphotase removes phosphate to switch protein off
GTP binds to replace GDP to switch protein on, GTP hydrolysis occurs to convert back to GDP bound form which is switched off
Integration devices
Some signalling proteins
Only when they receive signal from multiple pathways is there a response
