Positive and Negative Feedback

Question 1

What is feedback

Answer 1

1. Feedback is observed when the output from a given node follows a path of links that returns to regulate the node of origin.
2. Distinct from negative and positive regulation – regulation is a result of the pathway activity
3. How node can cause regulation upstream

Question 2

What is negative feedback

Answer 2

1. Output inhibits its own production

Question 3

What if a cell is stimulated with a sustained input?

Answer 3

1. In a normal, non adaptive response, output level increases with input and remains high during sustained input (the dynamic range of sensing is limited as the system reaches saturation).
2. By contrast, in an adaptive system, output level is transient as input increases (the system automatically resets to basal steady state, even with sustained input).

Question 4

What does the process of adaption/desensitisation mean

Answer 4

1. This process of adaption / desensitisation means that if the cell is stimulated with a sustained input:
2. Initial burst of output
3. Negative feedback occurs (after a short delay)
4. Output levels return to basal level (resets)
5. Even if the input stimulus remains at a high level

Question 5

How does responsiveness become reduced after an initial exposure?

Answer 5

1. Reduce receptor number

2. Prevent coupling to intracellular signaling pathways (reduce effective receptor number):

Question 6

How can you reduce receptor number

Answer 6

1. Endocytosis and sequestration of receptor in endosome

2. Destruction of receptor in lysosomes

Question 7

How can you reduce effective receptor number

Answer 7

1. Inactivation (e.g. by phosphorylation)
2. Inactivating downstream signaling
3. Production of inhibitor protein that blocks the pathway
4. (Typical of G-protein coupled receptor signalling for example)

Question 8

What is positive feedback

Answer 8

1. Output stimulates its own production

Question 9

What happens when graded responses are cooperative

Answer 9

1. Several cooperative modifications to become active
2. Each event more likely than the last (increased affinity)
3. Many signalling proteins are dependent on several cooperative modifications or binding events to become active.
4. Cooperativity - each binding or modification event is made more likely than the last.

Question 10

What are allosteric proteins

Answer 10

1. Allosteric proteins are proteins which have multiple-ligand binding site

Question 11

What are the 4 biochemical system types:

Answer 11

1. Hyperbolic
2. Ultrasensitive
3. Bistable
4. Oscillating

Question 12

What is a Hyperbolic system

Answer 12

1. In a hyperbolic system, a response to an increasing stimulus is initially linear but then levels off as the system becomes saturated.
2. Response increases as [ligand] increases
3. Plateau is reached if protein kinase activation sites become saturated

Question 13

What is an ultrasensitive system

Answer 13

1. Adds inhibitor to hyperbolic system
2. Inhibitor: can bind reversibly to the ligand, inhibiting it
3. An ultrasensitive system displays a sigmoidal dose-response curve because low levels of stimulus generate a poor response but higher levels generate an abrupt response.
4. Response is dampened at low [ligand]
5. Response rises abruptly when [ligand] ≥ [inhibitor]

Question 14

Describe a bistable system

Answer 14

1. Once kinase is activated by binding to ligand it can phosphorylate and thereby activate a second kinase
2. It can be a reversible phosphorylation
3. Activated Kinase: can activate more K, without ligand
4. Phosphatase: can inactivate activated K
5. Low [ligand]: phosphatase inactivates protein kinase
6. Increasing [ligand] doesn’t increase response much
7. At threshold [ligand], protein kinase activity overpowers phosphatase activity, regardless of the [ligand] once is has begun.
8. The signal continues without the initial stimulus (positive feedback)
9. A bistable system is able to exist stably in one of two alternate states, but cannot come to rest in an intermediate state between them.
10. This loop is self sustaining – if you remove input, the kinases would still remain active

Question 15

Give an example of bistability

Answer 15

1. Many transcription factors, once activated, can associate with their own promoters and promote their own transcription.
2. So for example, the initial input might activate TF1, which might drive the transcription of TF2, expression of TF2 might drive it’s own expression – this is really common.

Question 16

What is hysteresis

Answer 16

1. Molecular memory- hysteresis
2. Hysteresis - meaning delay or lagging behind
3. Hysteresis is the dependence of the state of a system on its history
4. The state of the system depends on its history and starting conditions

Question 17

What is an example of hysteresis

Answer 17

1. A bistable switch is an extreme form of hysteresis:
2. When input reaches a certain threshold, an output is achieved
3. When input reduced to original level – output is not diminished – system is self sustaining

Question 18

Describe an oscillating system

Answer 18

1. Combining positive and negative feedback results in a naturally oscillating, cycling system
2. Kinase can phosphorylate and activate an inhibitor
3. Activated K: can activate more K, without ligand (positive feedback)
4. Phosphatase: can inactivate K and Inhibitor
5. Inhibitor: activated by K, inhibiting the K (negative feedback)

Question 19

What does the graph of an oscillating system look like

Answer 19

1. Low [ligand]: phosphatase inactivates K
2. At threshold [ligand], K activity overpowers phosphatase activity. K induces more and more activated K by positive feedback, regardless of the [ligand] once is has begun.
3. After a delay, K phosphorylates and activates the inhibitor, inhibiting K activity (negative feedback) until it is low enough to become ligand-dependent again.

Question 20

When does an oscillating system work well

Answer 20

1. there is a delay before negative feedback

2. the activating signal is bistable (positive feedback)

Question 21

What are damped oscillations

Answer 21

1. Negative feedback with a small delay can cause damped oscillations
2. To get an oscillatory response in a system, we need:
3. Feedback
4. And the feedback must be delayed
5. If you follow the behaviour of these components over time
6. Initially oscillatory
7. Getting weaker over time
8. These are called damped oscillations

Question 22

What does increasing the delay of oscillations cause

Answer 22

1. Increasing the delay causes oscillations to become more stable
2. More components, so longer delay
3. Oscillations continue more stably over time (not damped)
4. In cells, negative feedback with a delay is a pre-requisite for oscillations