Some signaling systems are capable of generating a smoothly graded response over a wide range of extracellular signal concentrations (Figure 15–15, blue line); such systems are useful, for example, in the fine tuning of metabolic processes by some hormones. Other signaling systems generate significant responses only when the signal concentration rises beyond some threshold value. These abrupt responses are of two types. One is a sigmoidal response, in which low concentrations of stimulus do not have much effect, but then the response rises steeply and continuously at intermediate stimulus levels (Figure 15–15, red line). Such systems provide a filter to reduce inappropriate responses to low-level background signals but respond with high sensitivity when the stimulus falls within a small range of physiological signal concentrations. A second type of abrupt response is the discontinuous or all-or-none response, in which the response switches on completely (and often irreversibly) when the signal reaches some threshold concentration (Figure 15–15, green line). Such responses are particularly useful for controlling the choice between two alternative cell states, and they generally involve positive feedback, as we describe in more detail shortly.
Cells use a variety of molecular mechanisms to produce a sigmoidal response to increasing signal concentrations. In one mechanism, more than one intracellular signaling molecule must bind to its downstream target protein to induce a response. As we discuss later, for example, four molecules of the second messenger cyclic AMP must bind simultaneously to each molecule of cyclic-AMP-dependent protein kinase (PKA) to activate the kinase. A similar sharpening of response is seen when the activation of an intracellular signaling protein requires phosphorylation at more than one site. Such responses become sharper as the number of required molecules or phosphate groups increases, and if the number is large enough, responses become almost all-or-none (Figure 15–16).
Responses are also sharpened when an intracellular signaling molecule activates one enzyme and also inhibits another enzyme that catalyzes the opposite reaction. A well-studied example of this common type of regulation is the stimulation of glycogen breakdown in skeletal muscle cells induced by the hormone adrenaline (epinephrine). Adrenaline’s binding to a G-protein-coupled
Figure 15–14 The importance of rapid turnover. The graphs show the predicted relative rates of change in the intracellular concentrations of molecules with differing turnover times when their synthesis rates are either (A) decreased or (B) increased suddenly by a factor of 10. In both cases, the concentrations of those molecules that are normally degraded rapidly in the cell (red lines) change quickly, whereas the concentrations of those that are normally degraded slowly (green lines) change proportionally more slowly. The numbers (in blue) on the right are the half-lives assumed for each of the different molecules.
switchlike responses. Some cell responses increase gradually as the concentration of extracellular signal molecule increases, eventually reaching a plateau as the signaling pathway is saturated, resulting in a hyperbolic response curve (blue line). In other cases, the signaling system reduces the response at low signal concentrations and then produces a steeper response at some intermediate signal concentration—resulting in a sigmoidal response curve (red line). In still other cases, the response is more abrupt and switchlike; the cell switches completely between a low and high response, without any stable intermediate response (green line).
cell-surface receptor increases the intracellular concentration of cyclic AMP, which both activates an enzyme that promotes glycogen breakdown and inhibits an enzyme that promotes glycogen synthesis.