+ and - feedback Flashcards
feedback is distinct from..?
regulation
- ve feedback
- AKA
desensitisation / adaptation
what happens if a cell is stimulated with a sustained input?
nonadaptive response
adaptive response
nonadaptive response
increase in output
- > then plateaus
- > need higher level of input to increase output again
adaptive response
initial burst of output
-> -ve feedback
–> output levels return to basal
(even if stimulus remains high)
how does responsiveness become reduced after an initial exposure?
reduce receptor no.
block coupling to intracellular signalling pathway
reducing receptor no.
receptor sequestration in endosome
receptor destruction via lysosomes
blocks to intracellular signalling pathways
receptor inactivation
e.g. phosphorylation
inactivating intracellular signalling protein
-> prevents downstream signalling
produce inhibitory protein
- blocks pathway
+ feedback
- generates…
all or nothing response
allosteric proteins
- what do they need
have multiple ligand binding sites
need several cooperative modifications or binding events to be activated
each event increases input binding affinity
allosteric proteins
- low vs high ligand concs
low = less response
more binding events
-> steeper response curve
4 biochemical signalling system types
hyperbolic
ultrasensitive
bistable
oscillating
hyperbolic system
- stimulus
- response
ligand conc
- can bind reversibly to a kinase
protein kinase activity
hyperbolic system
- stimulus vs response graph
response increases as [ligand] increases
- initially linear
plateaus as kinases become saturated
ultrasensitive system
- what is it?
add a ligand inhibitor
- > reversibly sequesters ligand
- > less ligand to bind to kinase
ultrasensitive system
- response curve
sigmoidal shape
low levels of stimulus
-> poor response
when [ligand] > [inhibitor]
-> dramatic increase
high [ligand]
-> plateaus as all kinases saturated
bistable system
node in pathway activated
- > can up regulate own activation + phosphorylate other proteins
e. g. activate inactive kinase in absence of ligand
reversible
- ligand unbinds OR phosphatase remove activating P group
bistable system
- +ve feedback
once kinases phosphorylated + activated
-> can further phosphorylate kinases
bistable system
- response graph
all or nothing response
low [ligand]
- phosphatase inactivates kinase
increasing [ligand]
- response doesn’t increase much
threshold [conc]
- kinase activity > phosphatase activity
regardless of [ligand]
signal continues w/out initial stimulus
bistability
ability to exist in 2 distinct stable output states
w/out a stable intermediate steady state
2 examples of bistability
kinases
TFs
bistability example
- kinases
input phosphorylates + activates kinase 1
- > kinase 1 phosphorylates + activates kinase 2
- > response
kinase 2 also phosphorylates kinase 1
= self-sustaining loop
-> dramatic response curve
bistability example
- TF
activated
- > associate w/ own promoters
- > promote own transcription
input activates TF1
-> drives TF2 transcription
-> TF2 drives own transcription
= self-sustaining loop
self-sustaining loop
if remove input
-> kinases/TFs would remain active
hysteresis
= delay or lagging behind
- state of a system depends on its history + starting conditions
bistable switch
= extreme form of hysteresis
input reaches threshold
-> output
when input reduced to original level
-> output not diminished
= self-sustaining system
importance of + and - feedback
results in naturally oscillating cycling system
oscillating system
same as bistable system
BUT
active kinase phosphorylates + activates an inhibitor
inhibitor can repress the 2 kinases in the system
what is meant by oscillations?
output levels fluctuate between states of high + low activity in periodic manner
e.g. cell cycle
-ve feedback with small delay causes..?
how do you introduce a delay?
damped oscillations
add more components to pathway
-> takes longer for -ve feedback to initiate
-ve feedback with increased delay causes…?
more stable oscillations
- not damped
oscillating system
- response curve
low [ligand]
- phosphatase inactivates K
threshold [ligand]
- K activity > phosphatase activity
-> K induces more + more activated K via + feedback
(regardless of [ligand]
after delay, phosphatase activate inhibitor
-> represses K activity via -ve feedback
until low enough to be ligand-dependent again
+ve feedback systems
- how do they affect mitosis?
ensures all or nothing response
- cell starts mitosis or doesn’t
signal can continue w/out initial stimulus
- once cell starts mitosis, it will finish it
-ve feedback systems
can produce a repeating oscillator
oscillation works well if…:
there’s a delay before -ve feedback
activating signal is bistable (+ve feedback)
