Gap junction channels

In certain neurons, a different type of synapse, called a gap junction, may be formed. Gap junction transmission occurs through membrane channels made of six subunits, which directly connect with other postsynaptic gap junction channels. When the channels open, there is a continuity of cytoplasm and exchange of ions between the two neurons. This mode of transmission is faster because it does not involve the time-consuming processes of neurotransmitter release, diffusion across the synapse, and receptor binding. 

In summary, from the present point of view the most important mechanism for transmission of excitation is coupling via the gap junction channels. 

What is the role of the gap junctions By coupling the myocardial cells in both directions (longitudinal and transverse) they are responsible for the biophysical properties of the tissue. A reduction in gap junction distribution or a closure of the gap junction channels causes nonuniformities and discontinuities which alter the biophysical properties of the tissue and make it more prone to nonuniform anisotropic reentry. According to the model proposed by Krinsky [1966], a reduction in gap junctions or a closure of gap junction channels will lead to local slowing of conduction, thereby allowing smaller perimeters of reentrant arrhythmia. In addition, slowing of conduction is generally believed to be a risk factor for initiation of reentry. Since in many... 

In the following paragraphs several types of arrhythmia will be discussed with regard to the underlying mechanisms. Since it would be out of the scope of this book on gap junction channels to discuss all possible mechanisms of arrhythmia in detail, readers interested in a complete detailed review of the pathophysiology and clinics of arrhythmia are referred to the reviews by Janse and Wit [1989] and Pogwizd and Corr [1987, 1990] and to the specialized literature. 

At least three types of disturbance in the intercellular communication have to be distinguished (1) separation of the cardiac muscle fibers by strands of connective tissue as occurring in microfibrosis (2) changes in the distribution of gap junction channels, and (3) changes in the conductance of gap junctional channels either by alteration of the open probability or of the single channel conductance. 

Using the freeze fracture technique, electron microscopy and laser scanning confocal microscopy, it became obvious that these gap junctional channels are arranged as a cluster of channels with about 50 channels within one disk as stated by Gourdie et al. [1990]. 

From these studies and results Makowsky et al. [1977] developed a three-dimensional model for the channel. According to these studies the gap junction channels are arranged in clusters as shown in figure 3. A model of a single channel is given in figure 4. 

The next issue to discuss is the diversity of connexins, i.e. the various isoforms, and species variability. Gap junctional channels exist in a broad variety of tissues including the heart, vascular system, brain, epithelial tissues, uterus, lens cells, pancreas and kidney. However, these tissues are connected by different isoforms of gap junctional connexins which can be distinguished with regard to their molecular weight. These differences are mainly due to various lengths of the C-terminal loop. 

In some cases such variability has consequences for the regulation of the gap junction channels. Thus, in rat Cx32 the serine residue at position 233 is... 

In addition, myocytes and fibroblasts can form functional gap junction channels [Goshima, 1970] which has been experimentally investigated in gap junctions formed from both cells cultured from neonatal rat hearts [Rook et al., 1989]. It was found that the conductance between myocytes was in the order of 43 pS, between fibroblasts about 22 pS and between myocytes and fibroblasts in the range of 29 pS, indicating that a heterojunction may exist between both cell lines. Such heterojunctions are presently one of the main interests in gap junction research, since many physiological phenomena regarding crosstalk between various tissues and developmental phenomena may be involved. 

Gap junctional channels, like many other ion channels, can be modulated via second messengers and via phosphorylation processes. Besides these, intracellular calcium and pH have been proven to be important regulators of channel function. In this chapter the short-term regulatory processes are considered, i.e. processes on a time scale of minutes. Besides this, regulatory processes are known which take place over a period of 30 min up to several hours and which involve formation or synthesis of new gap junction channels. The latter processes are described in the following chapter. 

Gap junction conductance (gj) of neonatal rat heart cells varies with temperature (37 °C, 48.3 nS 14 °C, 21.4 nS -2°C, 17.5 nS) [Bukauskas and Weingart, 1993] so that gj has been assumed to be at least in part enzymatically controlled. Several protein kinases are known to be involved in the regulation of the gap junction channels. However, the situation is rather complicated since the same protein kinase may enhance or reduce gap junctional conductance in different tissues or in different species. Thus, generalizations should be avoided and the specific condition has to be taken into account. One of the first to be described was protein kinase A (PKA), the cAMP-dependent protein kinase, which can enhance junctional conductance in hepatocytes coupled via Cx32 and Cx26 [Saez et al., 1986, 1990]. Similarly, an increase in junctional conduc-... 

The cGMP-dependent PKG is also involved in the regulation of gap junction channels. Activation of PKG by cGMP or cGMP analogues, such... 

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