Amplification and attenuation of signals

The analogy between cellular signalling and electronic circuitry breaks down in one important respect. If A, B, C etc. in the schematic diagrams were electronic circuit components, there would normally be only one of each. But if they are signalling pathway intermediates this is not the case. A single activated receptor will usually activate many molecules of the type "M" Each "M" will activate several of type "A", each of which will activate several of type "B", and so on. Thus, a very tiny stimulus - the activation of a mere handful of receptors on the cell surface - can induce a very large response in a very short time.

Thus, cell signalling pathways generally amplify the external signals. The potential advantage can be seen, for example, in the effect of adrenaline on muscle cells. The leg muscles of a peacefully grazing herbivore use little energy, but the sudden appearance of a predator changes this situation swiftly and radically - this is obviously a matter of survival. The stimulus received by the muscle cells is a tiny increase in the adrenaline concentration in the blood stream. The response includes a huge, immediate increase in the rate of glycogen breakdown and the resulting production of ATP to fuel

17 We have used the words "activated" and "inactivated" throughout this chapter without explaining how a component might become activated. Although these details do not matter for the argument in the text, some readers might be curious. In most cases activation (more rarely, inactivation) is caused the addition of one or more phosphates to the protein. The phosphate is usually transferred from ATP. The activation is reversed when the phosphate is removed again. Thus, many signalling pathway components are, in effect, enzymes that cause phosphates to be added to or removed from one another. In other cases, where phosphate transfer is not involved, activation might be caused by the binding of the signalling protein to another protein or to a small metabolite molecule; or alternatively, its dissociation from such a molecule.

muscle contraction. The signalling pathway amplifies the glycogen-breakdown response to the adrenaline stimulus.

A cell might have many receptors for each stimulus. For example, a liver cell has a number of insulin receptors on the membrane surface in contact with the blood stream. The more insulin there is in the blood, the more of these receptors become occupied, so the greater the activation of the cell. Therefore, the cell's response to insulin rises with increasing concentrations of insulin in the blood stream. This sensible relationship holds for nearly all stimuli. As the dose of ligand increases, the cell's response increases until all the receptors are occupied.

However desirable the rapid amplified response to a signal might be, an "off switch" is also needed. It is seldom appropriate for the cell to go on responding to a single brief stimulus. There is no single "off switch", but a series of them. The ligand is often destroyed or otherwise removed, thus unloading the receptor; the unloaded receptor is converted back from the active R* to the inactive R form (or destroyed). Activated molecules (M) inside the cell are de-activated. Antagonistic signals are often brought into play, as we showed in Fig. 9-2. Negative feedback from later steps in the pathway can be used to inhibit earlier ones. And so on. These safeguards ensure that the response lasts long enough to bring about the requisite changes in the cell, but no longer. "Long enough" is typically seconds or a fraction of a second.

If the stimulus becomes excessive or abnormally prolonged in spite of these "off switches", the cell might adapt by eliminating some of its receptors. Unwanted receptors are sometimes detached from the membrane and dumped into the environment. In others cases they are pulled into the cell and digested by the lysosomes. In still others they are chemically inactivated. Whatever the method, receptor downgrading moderates the response. The cell adapts, i.e. becomes less responsive. This stops the cell "burning out" by sustaining its response to a pathologically prolonged stimulus.

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