Intercellular coupling

Oscillations of the segmentation clock with a period of 2 h have also been observed in fibroblast cell cultures following serum shock. There also, oscillations in the expression of the gene Hesl related to the Notch pathway have been attributed to negative feedback on transcription [171]. The periodic operation of the segmentation clock was recently demonstrated in cells of the PSM, where intercellular coupling is needed to prevent damping of the oscillations [172]. 

Anisotropy and nonuniformity are at least in part due to inhomogeneities in the distribution of gap junctions and the biophysical properties of the tissue are in fact influenced by the intercellular coupling. At least four features have to be considered. (1) Cardiac cells express different gap junction proteins (so-called connexins in the heart, connexin 40, connexin 43 and connexin 45 are most abundantly found for details see chapters 2 and 3). Channels formed by these connexins are different with regard to their biophysical properties. In various parts of the heart the content of each of these isoforms is different. 

An essential role for the normal cardiac development has recently been shown [Reaume et al., 1995] in mouse lacking Cx43 (see chapter 6). Intercellular coupling obviously is a prerequisite for the correct development. 

In contrast to cAMP, a stimulation of PKC with phorbol esters (TPA) has been shown to play an important role in the downregulation of gap junctional coupling [Yancey et al., 1982]. Since reestablishment of intercellular coupling was not seen after wash out of TPA in the presence of the protein synthesis inhibitor, puromycin [Fitzgerald et al., 1983], the phorbol ester probably induces the elimination of junctional channels under these conditions. Thus, it might be possible that PKC is involved in the regulation of channel degradation. 

Obviously, there is some kind of cross-talk between PKC and cAMP in the modulation of intercellular coupling, since cAMP can inhibit the uncoupling effect of phorbol esters if cells are exposed to both agents from the start of the experiment [Kanno et al., 1984], but this protective effect can be abolished by the protein synthesis inhibitor cycloheximide [Enomoto et al., 1984] in Balb/ cells. 

The immunohistochemical findings were correlated with reduced intercellular coupling indicating a possible role of disturbed Cx43 expression and gap junction function in the pathogenesis of Chagas disease and the arrhythmias associated with that disease. 

Thus, enhancing intercellular coupling may exert a prophylactic effect against arrhythmia if arrhythmia is due to uncoupling. However, if the coupling effect is unselective, it would probably postpone an impairing effect as discussed above for ischemia. From this theoretical point of view selective couplingenhancing effects on the previously uncoupled tissue would be desirable rather than unselective. 

In the following a survey is given of the substances which have been found to alter intercellular coupling. First drugs will be considered which uncouple gap junctions. A number of lipophilic compounds have been described to reduce gap junctional coupling. These substances include alcohols like hep-tanol and octanol, saturated and unsaturated fatty acids, and alcohols and... 

Similarly, De Mello [1989] reported on an improvement in intercellular coupling by the P-adrenoceptor agonist isoproterenol in cardiac cell pairs. Thus, stimulation of P-adrenoceptors can be assumed to result in enhancement of intercellular coupling, at least in some preparations. However, on the basis of the hndings of Kwak and Jongsma [1996] on a lack of the effect of PKA to alter gap junction conductance in rat cardiomyocytes, caution seems necessary and species variability or tissue variability seems to play an important role. 

Similar to a P-adrenoceptor stimulation intracellular cAMP can be increased by inhibition of phosphodiesterase. Thus, in turtle retina cells, cAMP leads to uncoupling and this can be mimicked by stimulation of adenylate cyclase with forskolin and concomitant inhibition of phosphodiesterase by IBMX [Piccolino et al., 1984]. In cardiac cells inhibition of phosphodiesterase has been investigated using methylxanthine derivates [De Mello, 1989], resulting in an enhancement of intercellular coupling. 

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Vigmond, E.J., Bardakjian, B.L., Thunberg, L., and Huizinga, J.D. 2000. Intercellular coupling mediated by potassium accumulation in peg-and-socket junctions. IEEE Trans. Biomed. Eng., 47 1576-1583. 

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In other tissues, many junction channels are present between coupled cells. Numbers vary from very few to hundreds or thousands. Furthermore, the nature of the connexins surrounding the intercellular pores is variable. In many instances there are hybrid channels (different connexins in one charmel) or charmels of different nature within one junction (24). This is important to understand the effects of different stimuli on intercellular coupling since a given stimulus does not necessarily act in identical form on different connexins. Furthermore, intercellular channels do not behave in an all-or-none manner since some may be totally or partially open as well as totally or partially closed. 

Figure 4 Effects of bethanechol (a) and dopamine (b) on intercellular coupling of two current-clamped glomus cells. The inset shows the experimental setup where Cell 1 was stimulated with positive pulses (Vi) and Cell 2 with negative pulses (V2). Vi produces a smaller deflection (E2) in coupled Cell 2. V2 elicits a smaller deflection (Ei) in coupled Cell 1. Ordinates, coupling coefficients (K ). Open squares, coupling from 1 to 2. Open circles, coupling fi"om 2 to 1. Abscissa, time in seconds.

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