Under what conditions will a target cell always respond quickly to an extracellular signal?

  Cells Can Respond Abruptly to a Gradually Increasing Concentration of an Extracellular Signal

Some cellular responses to extracellular signal molecules are smoothly graded in simple proportion to the concentration of themolecule. The primary responses to steroid hormones often follow this pattern, presumably because the nuclearhormone receptor protein binds a single molecule of hormone and each specific DNA recognition sequence in a steroid-hormone-responsive gene acts independently. As the concentration of hormone increases, the concentration of activated receptor-hormone complexes increases proportionally, as does the number of complexes bound to specific recognition sequences in the responsive genes; the response of the cell is therefore a gradual and linear one. Many responses to extracellular signal molecules, however, begin more abruptly as the concentration of the molecule increases. Some may even occur in a nearly all-or-none manner, being undetectable below a threshold concentration of the molecule and then reaching a maximum as soon as this concentration is exceeded. What might be the molecular basis for such steep or even switchlike responses to graded signals?

One mechanism for sharpening the response is to require that more than one intracellular effector molecule or complex bind to some target macromolecule to induce a response. In some steroid-hormone-induced responses, for example, it seems that more than one activated receptor-hormone complex must bind simultaneously to specific regulatory sequences in the DNA to activate a particulargene. As a result, as the hormone concentration rises, gene activation begins more abruptly than it would if only one bound complex were sufficient for activation. A similar cooperative mechanism often operates in the signaling cascades activated by cell-surface receptors. As we discuss later, four molecules of the small intracellular mediator cyclic AMP, for example, must bind to each molecule of cyclic-AMP-dependent protein kinase to activate the kinase. Such responses become sharper as the number of cooperating molecules increases, and if the number is large enough, responses approaching the all-or-none type can be achieved

When activated, estradiol receptors turn on the transcription of several genes. Dose-response curves for two of these genes are shown, one coding for theegg protein conalbumin and the other coding for the egg protein ovalbumin. The linear response curve for conalbumin indicates that each activated receptormolecule that binds to the conalbumin gene increases the activity of the gene by the same amount. In contrast, the lag followed by the steep increase in the response curve for ovalbumin suggests that more than one activated receptor (in this case, two receptors) must bind simultaneously to the ovalbumin gene to initiate its transcription. (Adapted from E.R. Mulvihill and R.D. Palmiter, J. Biol. Chem. 252:2060-2068, 1977.)

The curves show how the sharpness of the response increases with an increase in the number of effector molecules that must bind simultaneously to activate a target macromolecule. The curves shown are those expected if the activation requires the simultaneous binding of 1, 2, 8, or 16 effector molecules.

Here, the simultaneous binding of eight molecules of a signaling ligand to a set of eight protein subunits is required to form an active protein complex. The ability of the subunits to assemble into the active complex depends on an allosteric conformational change that the subunits undergo when they bind their ligand. The binding of the ligand in the formation of such a complex is generally a cooperative process, causing a steep response as the ligand concentration is changed, as explained in Chapter 3. At low ligand concentrations, the number of active complexes increases roughly in proportion to the eighth power of the ligand concentration.

Responses are also sharpened when an intracellular signaling molecule activates one enzyme and, at the same time, inhibits another enzyme that catalyzes the opposite reaction. A well-studied example of this common type of regulation is the stimulation of glycogenbreakdown in skeletal muscle cells induced by the hormone adrenaline (epinephrine). Adrenaline's binding to a G-protein-linked cell-surface receptor leads to an increase in intracellular cyclic AMP concentration, which both activates an enzyme that promotes glycogen breakdown and inhibits an enzyme that promotes glycogen synthesis.

All of these mechanisms can produce responses that are very steep but, nevertheless, always smoothly graded according to the concentration of the extracellular signal molecule. Another mechanism, however, can produce true all-or-none responses, such that raising the signal above a critical threshold level trips a sudden switch in the responding cell. All-or-none threshold responses of this type generally depend on positive feedback; by this mechanism, nerve and muscle cells generate all-or-none action potentials in response to neurotransmitters (discussed in Chapter 11). The activation of ion-channel-linked acetylcholine receptors at aneuromuscular junction, for example, results in a net influx of Na+ that locally depolarizes the muscle plasma membrane. This causes voltage-gated Na+ channels to open in the same membrane region, producing a further influx of Na+, which further depolarizes the membrane and thereby opens more Na+ channels. If the initial depolarization exceeds a certain threshold value, this positive feedback has an explosive "runaway" effect, producing an action potential that propagates to involve the entire muscle membrane. An accelerating positive feedback mechanism can also operate through signaling proteins that are enzymes rather than ion channels. Suppose, for example, that a particular intracellular signaling ligand activates an enzyme located downstream in a signaling pathway and that two or more molecules of the product of the enzymatic reaction bind back to the same enzyme to activate it further (Figure 15-24). The consequence is a very low rate of synthesis of the product in the absence of the ligand. The rate increases slowly with the concentration of ligand until, at some threshold level of ligand, enough of the product has been synthesized to activate the enzyme in a self-accelerating, runaway fashion. The concentration of the product then suddenly increases to a much higher level. Through these and a number of other mechanisms not discussed here, the cell will often translate a gradual change in the concentration of a signaling ligand into a switchlike change, creating an all-or-none response by the cell.

An accelerating positive feedback mechanism. In this example, the initial binding of the signaling ligand activates the enzyme to generate a product that binds back to the enzyme, further increasing the enzyme's activity.

The effect of an extracellular signal on a target cell can, in some cases, persist well after the signal has disappeared. The enzymatic accelerating positive feedback system just described represents one type of mechanism that displays this kind of persistence. If such a system has been switched on by raising the concentration of intracellular activating ligand above threshold, it will generally remain switched on even when the extracellular signal disappears; instead of faithfully reflecting the current level of signal, the response system displays a memory. We shall encounter a specific example of this later, when we discuss a protein kinase that is activated by Ca2+ to phosphorylate itself and other proteins; the autophosphorylation keeps the kinase active long after Ca2+ levels return to normal, providing a memory trace of the initial signal. Transient extracellular signals often induce much longer-term changes in cells during the development of a multicellular organism. Some of these changes can persist for the lifetime of the organism. They usually depend on self-activating memory mechanisms that operate further downstream in a signaling pathway, at the level of gene transcription. The signals that trigger muscle cell determination, for example, turn on a series of muscle-specific gene regulatory proteins that stimulate the transcription of their own genes, as well as genes producing many other muscle cell proteins. In this way, the decision to become a muscle cell is made permanent.

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 very wide range of stimulus intensities. This requires that the target cells undergo a reversible process of adaptation, or desensitization, whereby a prolonged exposure to a stimulus decreases the cells' response to that level of exposure. In chemical signaling, adaptationenables cells to respond to changes in the concentration of a signaling ligand (rather than to the absolute concentration of the ligand) over a very wide range of ligand concentrations. The general principle is one of a negative feedback that operates with a delay. A strong response modifies the machinery for making that response, such that the machinery resets itself to an off position. Owing to the delay, however, a sudden change in the stimulus is able to make itself felt strongly for a short period before the negative feedback has time to kick in.

Desensitization to a signal molecule can occur in various ways. Ligand binding to cell-surface receptors, for example, may induce their endocytosis and temporary sequestration in endosomes. Such ligand-induced receptor endocytosis can lead to the destruction of the receptors in lysosomes, a process referred to as receptor down-regulation. In other cases, desensitization results from a rapid inactivation of the receptors-for example, as a result of a receptor phosphorylation that follows its activation, with a delay. Desensitization can also be caused by a change in a protein involved in transducing the signal or by the production of an inhibitor that blocks the transduction process

The inactivation mechanisms shown here for both the receptor and the intracellular signaling protein often involve phosphorylation of the protein that is inactivated, although other types of modification are also known to occur. In bacterial chemotaxis, which we discuss later, desensitization depends on methylation of the receptor protein. Having discussed some of the general principles of cell signaling, we now turn to the G-protein-linked receptors.

These are by far the largest class of cell-surface receptors, and they mediate the responses to the great majority of extracellular signals. This superfamily of receptor proteins not only mediates intercellular communication; it is also central to vision, smell, and taste perception.

Summary

Each cell in a multicellular animal has been programmed during development to respond to a specific set of extracellular signals produced by other cells. These signals act in various combinations to regulate the behavior of the cell. Most of the signals mediate a form of signaling in which local mediators are secreted, but then are rapidly taken up, destroyed, or immobilized, so that they act only on neighboring cells. Other signals remain bound to the outer surface of the signaling cell and mediate contact-dependent signaling. Centralized control is exerted both by endocrine signaling, in which hormones secreted by endocrine cells are carried in the blood to target cells throughout the body, and by synaptic signaling, in which neurotransmitters secreted by nerve cell axons act locally on the postsynaptic cells that the axons contact.

Cell signaling requires not only extracellular signal molecules, but also a complementary set of receptor proteins in each cell that enable it to bind and respond to the signal molecules in a characteristic way. Some small hydrophobic signal molecules, includingsteroid and thyroid hormones, diffuse across the plasma membrane of the target cell and activate intracellular receptor proteins that directly regulate the transcription of specific genes. The dissolved gases nitric oxide and carbon monoxide act as local mediators by diffusing across the plasma membrane of the target cell and activating an intracellular enzyme-usually guanylyl cyclase, which produces cyclic GMP in the target cell. But most extracellular signal molecules are hydrophilic and can activate receptor proteins only on the surface of the target cell; these receptors act as signal transducers, converting the extracellular binding event into intracellular signals that alter the behavior of the target cell.

There are three main families of cell-surface receptors, each of which transduces extracellular signals in a different way. Ion-channel-linked receptors are transmitter-gated ion channels that open or close briefly in response to the binding of a neurotransmitter. G-protein-linked receptors indirectly activate or inactivate plasma-membrane-bound enzymes or ion channels via trimeric GTP-binding proteins (G proteins). Enzyme-linked receptors either act directly as enzymes or are associated with enzymes; these enzymes are usually protein kinases that phosphorylate specific proteins in the target cell.

Once activated, enzyme- and G-protein-linked receptors relay a signal into the cell interior by activating chains of intracellular signaling proteins; some transduce, amplify, or spread the signal as they relay it, while others integrate signals from different signaling pathways. Many of these signaling proteins function as switches that are transiently activated by phosphorylation or GTP binding. Functional signaling complexes are often formed by means of modular binding domains in the signaling proteins; these domains allow complicated protein assemblies to function in signaling networks.

Target cells can use a variety of intracellular mechanisms to respond abruptly to a gradually increasing concentration of an extracellular signal or to convert a short-lasting signal into a long-lasting response. In addition, through adaptation, they can often reversibly adjust their sensitivity to a signal to allow the cells to respond to changes in the concentration of a particular signal molecule over a large range of concentrations.

Under what condition will a target cell always respond quickly to an extracellular signal?

What does a target cell require to respond to an extra cellular signal molecule?

Under what conditions will the target gene for this signaling network be expressed?

What is extracellular signaling?