Adaptation to constant stimuli

Goldbeter, 1989). oscillations, which often have a period of the order of minutes, have been observed in a number of different cell types this oscillatory phenomenon is discussed in detail in chapter 10. A direct link between Ca oscillations and cAMP would exist because inositol 1,4,5-trisphosphate (IP3), whose synthesis is elicited by the cAMP stimulus (Europe-Finner Newell, 1987), controls the mechanism of Ca spiking (see chapter 10). Oscillations of extracellular Ca have been recorded in D. discoideum suspensions (Bumann, Malchow Wurster, 1986 Wurster, 1988), but periodic variations of intracellular Ca have not yet been observed. 

That the activation of adenylate cyclase by extracellular cAMP plays an essential role in the mechanism of cAMP oscillations is nevertheless demonstrated by the inhibition of periodic behaviour by adenosine, which interferes with cAMP binding to the receptor (Newell, 1982 Newell Ross, 1982), and by caffeine (Theibert Devreotes, 1983 Brenner Thoms, 1984 Kimmel, 1987), which uncouples the receptor from adenylate cyclase. 

Despite its necessarily incomplete nature, it appears that the model analysed above for the synthesis of cAMP in D. discoideum amoebae is based on the most conspicuous properties of the signalling system, namely self-amplification due to the activation of adenylate cyclase that follows the binding of cAMP to the receptor, and desensitization of this receptor through cAMP-induced phosphorylation. 

As the model based on desensitization of the cAMP receptor accounts well for excitable and oscillatory behaviour in the synthesis of cAMP in D. discoideum, it is necessary to test its predictive power for the types of response observed in other experimental conditions. In particular, it remains to be shown whether the model can account for the response of cells subjected to constant stimulation by cAMP. 

The instructive series of experiments carried out by Devreotes and coworkers (Devreotes Steck, 1979 Dinauer etal., 1980a,b,c Theibert Devreotes, 1983) has permitted the determination of the time evolution of cAMP synthesis in the absence of the positive feedback loop that is normally exerted by extracellular cAMP (compare fig. 5.37b and c). Although such unphysiological conditions do not occur during the life cycle of D. discoideum, they nevertheless yield highly useful information on the various factors that control the synthesis of cAMP in the 

---

Fig. 5.38. Adaptation to constant stimuli. At time zero, the system is subjected to an increase in extracellular cAMP, y, whose level rises from zero to 0.1 (curve a), 1 (curve b) and 10 (curve c). For = 10" M, these stimuli correspond to the passage from the cAMP level from zero to 10" M, 10 M, and lO M, respectively. The synthesis of intracellular cAMP resulting from these stimulations is indicated the responses are characterized by the phenomenon of adaptation. In inset, the evolution of fraction Sj indicates that adaptation correlates with receptor modification. The magnitude of receptor desensitization increases with the intensity of stimulation. The curves are obtained by numerical integration of the two-variable system (5.16) for the parameter values given in table 5.3 (Martiel Goldbeter, 1987a).

Incorporation of the role of G-proteins in transduction of the cAMP signal therefore allows us to account both for the results of experiments on oscillations and on adaptation to constant stimuli. With the exception mentioned above (see fig. 5.42), most experimental results can, however, be accounted for in a satisfactory manner when the role of G-proteins is not explicitly incorporated into the model for cAMP signalling. The model based on receptor desensitization thus permits us to unify the different types of dynamic behaviour observed under various... 

The first model proposed for the phenomenon of adaptation to constant stimuli, due to Katz Thesleff (1957), sought to explain the desensitization of the acetylcholine receptor following prolonged incubation of the receptor with its ligand. This model was based on the existence of two conformational states of the receptor, one of which is desensitized and possesses a reduced capacity to induce the cellular response. Experimental data confirm the existence of multiple conformational states of the acetylcholine receptor (Changeux, 1981), although these data reveal that the situation is more complex than that considered in the initial model. 

As in the case of bacterial chemotaxis, where receptor methylation acts as a counterbalance to changed external conditions and thus allows the cells to adapt to constant stimulation (Koshland, 1980), phosphorylation of the cAMP receptor provides the counterbalance thanks to which D. discoideum amoebae adapt to constant cAMP stimuli. 

When desensitization is due to some covalent modification, the particular condition (8.7) does not necessarily hold, because the direct and reverse steps in the cyclical system correspond to the direct steps of distinct reactions catalysed by different enzymes (Segel et al, 1986 Waltz Caplan, 1987). Thus, in the case of receptor phosphorylation in Dictyostelium, the constants k, 2 and k, k 2 relate, respectively, to the direct steps of the reactions catalysed by the protein kinase and by the phosphatase, reactions for which the reverse steps are being neglected. Conditions (8.6) then suffice to ensure exact adaptation for all stimuli, as indicated by fig. 8.7 and by fig. 8.8a where the changes in the activity are shown, in response to stimuli of increasing magnitude. 

Adaptation—the process of recovery from a stimulated behavior when the stimulus is still present—is essential for every behavioral system. It allows detection of small changes in the stimulus level on top of existing, constant level of stimulation. In the case of bacterial chemotaxis, adaptation enables bacteria to respond to new stimuli in the presence of constant levels of chemoattractants and/or chemorepellents. 

Sensory Organs. Man continously receives information about the environment as well as about himself, both voluntary and involuntary. These are transmitted by the sensory organs. Special receptors—mechanoreceptors, photoreceptors, thermoreceptors, and chemoreceptors—react to possible stimuli and convert the information into electrical impulses. The frequencies of these impulses are influenced by the intensity of the stimulus and its rate of change. Sensory nerves transmit these impulses to the brain where they are registered and processed as conscious sensations. Whenever constant stimuli act for a prolonged period of time, the impulse frequency of the receptor and the intensity of the sensation will be reduced. This means the receptor has adapted itself. 

---