The Mechanisms of Intercellular Communication

A target cell that receives a signal within the framework of intercellular communication transmits the signal in intracellular pathways. The intracellular signaling pathways are characterized by the following parameters  

The sum of these reactions determines the response of the target cell. 

Cells can receive and process signals in the form of messenger substances (proteins, low-molecular-weight substances), and electrical, optical and other stimuli. 

Specialized proteins, termed receptors, are utilized for the reception of signals. The reception of the signals by the receptor is equivalent to the binding of messenger 

There are two principal ways by which target cells can process incoming signals  

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The first model proposed for the mechanism of intercellular communication in D. discoideum (fig. 5.10) successfully predicted the existence of sustained oscillations of cAMP (Goldbeter, 1975). The experimental data on which that model was based, however, turned out to be partly inexact due to an experimental artefact. Although the theoretical prediction of cAMP oscillations was soon corroborated by the observations of Gerisch Wick (1975), the source of the oscillations lay in another regulatory mechanism that remained to be determined. 

Experimentally, the mechanism of intercellular communication by cAMP pulses in the course of D. discoideum aggregation is characterized by its periodicity. The latter is reflected by the wavelike movement of amoebae towards the aggregation centres, as a result of the periodic pulses of cAMP that the latter emit at regular intervals (Durston, 1974a). The periodic behaviour of the model based on receptor desensitization accounts for the periodic secretion of cAMP by aggregation centres, whereas excitable behaviour accounts for the relay of cAMP pulses by cells that amplify the suprathreshold signals emitted by the centres. 

Fig. 7.3. Evolution of the biochemical parameters of the mechanism of intercellular communication during the hours that follow starvation in D. discoideum. The variation in the activity of (a) adenylate cyclase and (b) intra- and extracellular phosphodiesterase and (c) the evolution of the quantity of cAMP receptor measured in experiments performed with two different levels of cAMP. In (b), circles and triangles refer to total phosphodiesterase and to a protein inhibitor of the enzyme, respectively closed symbols relate to cells treated by pulses of cAMP resulting in 10" M cAMP every 5 min, whereas open symbols relate to untreated cells (data collected from various authors by Loomis, 1979).

Fig. 7.4. Developmental path for the mechanism of intercellular communication by cAMP signals in D. discoideum, in agreement with the variations observed for the activity of adenylate cyclase and phosphodiesterase after starvation. The diagram is constructed as indicated in fig. 7.2, for system (5.1) to which the term (-k a) has been added in the evolution equation for variable a, to take into account the utilization of ATP to ends other than cAMP synthesis. In these conditions, the developmental path accounting for the sequential transitions of fig. 7.1 corresponds to the increase in the two enzyme activities that is observed in the hours that follow starvation (fig. 7.3). Domains A, B and C have the same meaning as in fig. 7.2 domain D corresponds to a stable steady state characterized by an elevated level of cAMP, while two stable steady states can coexist in E. The signal considered for amplification in B is y = 10. Parameter values are V = 0.04 s, k, - 0.4 s k = 10" s", = 10, L = lO", q = 100 (Goldbeter Segel, 1980).

Fig. 7.5. Incorporating the variation of biochemical parameters into the description of the evolution of the mechanism of intercellular communication in D. dis-coideum. The sigmoidal increase observed during the 6h that follow the beginning of starvation for adenylate cyclase (

Goldbeter, A. J.L. Martiel. 1987. Periodic behaviour and chaos in the mechanism of intercellular communication governing aggregation of Dictyostelium amoebae. In Ghaos in Biological Systems. H. Degn, A.V. Holden L.F. Olsen, eds. Plenum Press, New York, pp. 79-89. 

Acetylcholine is involved in many aspects of the regulation of the cardiovascular system. Thus, it may also play a role in the control of intercellular communication. Very early in gap junction research the effect of acetylcholine as an important transmitter on gap junction conductance has been investigated. First, Petersen and Ueda [1976] demonstrated an increase in junctional resistance in pancreatic acinar cells following the application of acetylcholine. Concomitantly, the release of amylase was stimulated. A minimum concentration of 1 pmol/l acetycholine was required to evoke uncoupling. The next question was, how is the acetylcholine effect mediated Calcium has been considered to contribute to the mechanism of action [Iwatsuki and Pertersen,... 

Fig. 3.1 Pri ncipal mechanisms of intercellular communication, a) communication via intercellular messengers, b) communication via gap junctions. Gap junctions are direct connections between cells. They are coated by proteins (drawn as circles in the figure above) that can have a regulatory influence on the transport, c) communtication...

Bacteria, as well as fungi, can only transport simple monomers and some dimers across their cell walls and as such must excrete a suite of extracellular enzymes to break down large and complex organic molecules (discussed in detail in Section 8.07.5). The production of extracellular enzymes by an individual microbe can be seen as a metabolically costly and potentially wasteful process. However, many bacteria have developed mechanisms for intercellular communication that allow homogenous populations to coordinate... 

The antioxidant alkaloids boldine and its dimethoxy analogue glaucine (43) inhibit TPA-induced down-regulation of gap junctional intercellular communication in WB-F344 rat liver epithelial cells in a dose-dependent manner. Analysis of the mechanism of action of these agents revealed that boldine and glaucine at 10 )j.M totally inhibited the TPA-induced accumulation of intracellular oxidants. In addition, these alkaloids at 50 jM inhibited TPA-induced translocation of PKC to the particulate fraction of the cells [107]. 

As discussed in Chapter 16, the question of whether or not athermal levels of microwave fields are toxic is a controversial one. One study, however, found that such microwaves act synergistically with chemical cancer promoters and lead to autonomous cell growth. 711 This effect has been demonstrated in vitro using the combination of cancer promoting phorbol esters co-applied with nonionizing electromagnetic fields. The author of the study hypothesizes that the mechanism of the combined radiation/ chemical effect involves the disruption of normal intercellular communication through gap junctions. 

A further intercellular communication mechanism relies on electrical processes. The conduction of electrical impulses by nerve cells is based on changes in the membrane potential. The nerve cell uses these changes to communicate with other cells at specialized nerve endings, the synapses. It is central to this type of intercellular communication that electrical signals can be transformed into chemical signals. This type of communication will not be discussed in this book. 

The cell has other transmembrane receptors and signaling pathways that do not fit into the classical receptor types and signal mechanisms described in Chapters 5-11. The following signaling pathways certainly do not complete the list of intercellular and intracellular communication mechanisms in mammals, and it is to be expected that other classes of signaling pathways will be described in the future. 

Previous chapters deal with several important topics, for example, the metabolism of carbohydrates, lipids, and other molecules. However, the whole is not just the sum of its parts. Multicellular organisms are extraordinarily complex, more so than their components would suggest. Chapter 16 takes a wider view of functioning of the mammalian body. Initially, the division of labor that allows the sophisticated functioning of the multicellular body is considered. This is followed by a discussion of the feedingfasting cycle, a complex multiorgan process. Hormones and growth factors, the major tools of intercellular communication, and their mechanisms of action are then described. Chapter 16 also includes a discussion of diabetes mellitus, a disease that has widespread metabolic effects. 

In contrast to genotoxic carcinogens, epigenetic carcinogens act by a wide variety of mechanisms. Some of the possible epigenetic mechanisms of chemical carcinogenesis include peroxisome proliferation, inhibition of intercellular communication, microtubule alteration, hormonal imbalance, cytotoxicity, immunomodulation, inhibition of DNA methylation, etc. 

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