Figure 15–18 Some effects of simple feedback. The graphs show the computed effects of simple positive and negative feedback loops (see Chapter 8). In each case, the input signal is an activated protein kinase (S) that phosphorylates and thereby activates another protein kinase (E); a protein phosphatase (I) dephosphorylates and inactivates the activated E kinase. In the graphs, the red line indicates the activity of the E kinase over time; the underlying blue bar indicates the time for which the input signal (activated S kinase) is present.
(A) Diagram of the positive feedback loop, in which the activated E kinase acts back to promote its own phosphorylation and activation; the basal activity of the I phosphatase dephosphorylates activated E at a steady, low rate. (B) The top graph shows that, without feedback, the activity of the E kinase is simply proportional (with a
E kinase E kinase I phosphatase short lag) to the level of stimulation by the S kinase. The bottom graph shows that, with the positive feedback loop, the transient stimulation by S kinase switches the system from an “off” state to an “on” state, which then persists after the stimulus has been removed. (C) Diagram of the negative feedback loop, in which the activated E kinase phosphorylates and activates the I phosphatase, thereby increasing the rate at which the phosphatase dephosphorylates and inactivates the phosphorylated E kinase. (D) The top graph shows, again, the response in E kinase activity without feedback. The other graphs show the effects on E kinase activity of negative feedback operating after a short or long delay. With a short delay, the system shows a strong, brief response when the signal is abruptly changed, and the feedback then drives the response back down to a lower level. With a long delay, the feedback SIGNAL produces sustained oscillations for as long (D) as the stimulus is present.
0 0.001 0.01 0.1 1 10 progesterone (µM) increasing concentration of progesterone (A) operates more powerfully. A delayed negative feedback with a long enough delay can produce responses that oscillate. The oscillations may persist for as long as the stimulus is present (Figure 15–18C and D) or they may even be generated spontaneously, without need of an external signal to drive them. Many such oscillators also contain positive feedback loops that generate sharper oscillations. Later in this chapter, we will encounter specific examples of oscillatory behavior in the intracellular responses to extracellular signals; all of them depend on negative feedback, generally accompanied by positive feedback.
If negative feedback operates with a short delay, the system behaves like a change detector. It gives a strong response to a stimulus, but the response rapidly decays even while the stimulus persists; if the stimulus is suddenly increased, however, the system responds strongly again, but, again, the response rapidly decays. This is the phenomenon of adaptation, which we now discuss.
Cells Can Adjust Their Sensitivity to a Signal
In responding to many types of stimuli, cells and organisms are able to detect the same percentage of change in a signal over a wide range of stimulus strengths. The target cells accomplish this through a reversible process of adaptation, or desensitization, whereby a prolonged exposure to a stimulus decreases the cells’ response to that level of stimulus. In chemical signaling, adaptation enables cells to respond to changes in the concentration of an extracellular signal molecule (rather than to the absolute concentration of the signal) over a very wide range of signal concentrations. The underlying mechanism is negative feedback that operates with a short delay: a strong response modifies the signaling machinery involved, such that the machinery resets itself to become less responsive to the same level of signal (see Figure 15–18D, middle graph). Owing to the delay, however, a sudden increase in the signal is able to stimulate the cell again for a short period before the negative feedback has time to kick in.