Biomedical Engineering Reference
In-Depth Information
tion). Through secretion, this in turn leads to a significant increase in
γ
.
Through this amplification mechanism, the MG model permits propagation
of pulses in spatially extended systems, which we will discuss in more de-
tail in the next section. We should point out here that excitability occurs in
many different systems including cardiac excitation and nerve impulse, and
the theory and modeling of these phenomena are extremely active fields.
The MG has become the de facto model, in particular when examining
spatially extended systems. This, however, does not mean that the MG model
captures the precise workings of the relay mechanism and a number of ob-
jections can be raised. First of all, there is the aforementioned assumption of
dimeric activation, for which, no experimental evidence exists to date. Second,
experiments clearly indicate that there is a 30-60 s time lag between the bind-
ing of cAMP to CAR1 and the ACA activation. The origin of this time lag is
not well understood but it is clear that a large number of steps exists between
the ligand binding and ACA activation. Third, the original MG model is not
able to capture the adaptation of Dicty cells to continuing and varying cAMP
stimuli. As demonstrated by Devreotes and Steck [7], when cells in suspension
were presented with extracellular levels of cAMP that were held constant for
225 s and increased stepwise from zero to 10
−
6
M, the excreted cAMP levels
rose rapidly after each increase in external cAMP but reduced to previous lev-
els before the next increase. Thus, the cAMP relay machinery adapts within
roughly four minutes, after which it can respond again to a higher level of
extracellular cAMP. Furthermore, recent data on mutants that contain non-
phosphorable receptors cast serious doubt on the role phosphorylation plays
in adaptation [8]. In these mutants, adaptation of ACA activity was found
to be identical to the one in wild-type cells, thus indicating that the primary
mechanism for adaptation does not depend on the phosphorylation of cAMP
receptors.
Because of these shortcomings, several other groups have produced alter-
native models, and Martiel and Goldbeter themselves have attempted to ex-
tend their work to include adaptation. Of particular note is the Tang-Othmer
approach which dispenses with the suspect dimerization step, but nonethe-
less appeals to unknown biology in the form of a receptor that binds cAMP
and generates an inhibitory signal [9]. This extra pathway is needed to get
the adaptation. Also, a strong nonlinearity is postulated for the cAMP secre-
tion, with no obvious biological motivation. A third approach is that of Laub
and Loomis, who used only known biological components to produce a cAMP
oscillation [10]. There is still no adaptation and still no delay in cAMP pro-
duction. More importantly, this model does not have an excitable phase and
hence cannot transmit waves if the cells would not be spontaneously oscillat-
ing by themselves. It is also important to realize that even this more detailed
molecular approach ignores many known facts regarding the internal spatial
locations of various parts of the chemical pathway (for example, the fact that
activated ACA is localized at the rear of the cell); how important these will
prove to be is uncertain.
