Necessity of amending the allosteric model for cAMP signalling

4 Necessity of amending the allosteric model for cAMP signalling 

To understand the reasons why it is necessary to modify the hypotheses on which the allosteric model for cAMP signalling is based, it is useful to define more precisely the mechanism that underlies oscillations in this model. 

Any rhythm can be comprehended as a sequence of two phases that merge and follow each other in an autonomous manner. The first phase, of amplification, corresponds here to the onset of a peak in cAMP synthesis. The second phase, of limitation, corresponds to the decrease in cAMP synthesis, once the maximum is passed. Autonomous oscillations occur because of the regenerative process that leads to the renewal of the self-amplification phase after cAMP has reached its minimum level. To understand the mechanism of oscillations is tantamount to identifying this regenerative process as well as those responsible for self-amplification and for its limitation. 

Substrate availability as a factor limiting self-amplification 

The discussion of the two-variable system (5.4b,c) helps to clarify the sequence of events. When the term which denotes the rate of cAMP synthesis in eqn (5.4c), is exceeded by the term ky, which denotes cAMP hydrolysis by phosphodiesterase, the level of extracellular cAMP begins to decrease. There results a further decrease in the rate of synthesis, because of the diminished binding of cAMP to the receptor and of the subsequent reduction in adenylate cyclase activation this further accelerates the drop in cAMP. When cAMP reaches its minimum, adenylate cyclase functions at a basal rate (in the absence of activation by the receptor free from cAMP) the substrate can re-accu-mulate, since its rate of input then exceeds its rate of consumption in the reaction catalysed by adenylate cyclase. When extracellular cAMP has itself accumulated so as to reach a level where its binding to the receptor begins to significantly activate adenylate cyclase, self-amplification resumes and a new cycle of oscillations begins. 

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