cell types that are subjected to stress or shear (e.g., cardiac muscle, epithelium of skin, cervix of the vagina). The following electron microscope picture (left) is false-colored (right) to show the different components of the desmosome more clearly (Figure 3.12).
The paired dark masses that reside on opposite sides of the intercellular space are called desmosomal adhesion plaques. Early work showed that mild digestion with dilute protein digesting enzymes (proteases), such as trypsin, caused the desmosomes to disappear and the cells to separate. Thus it became clear that these structures were primarily made up of proteins involved in cell adhesion. The adhesion plaques link to tonofilaments in the cytoplasm. It was discovered that the tonofilaments are keratin intermediate filaments, so both terms are used when desmosomes are discussed.
Figure 3.12. The ultrastructure of a desmosome.
Adhesion between cells is mediated by desmogleins and desmocollins which are desmosomal forms of cadherins (Figure 3.13). These extend from the cell membrane across the intercellular space. They differ from other cadherins in their intracellular domains which is why desmosomal cadherins associate with keratin while those in adherens junctions are linked to actin filaments. The dense plaques on the inner side of the membrane are sites where the desmoplakin and plakoglobin linker molecules link the cytoplasmic tails of the desmogleins and desmocollins to the tonofilaments (keratin intermediate filaments). Plakoglobin for example is very similar to ß-catenin.
Figure 3.13. The structure of a desmosome and its protein components.
A close-up of the proteins found in desmosomes is shown in the following figure (Figure 3.14). Homotypic binding occurs between the desmosomal cadherins desmoglein and desmocolin.
Figure 3.14. The organization of desmosomal proteins.
Desmosomes and Disease
Because desmosomes show such precise localizations and since they appear to have a consistent structure, we tend to think of them as static and uninteresting structures. This is compounded by other issues: they are linked to tight cell adhesions which maintain tissue integrity in the gut and other areas. But detailed studies using immunolocalization of desmosomes show their localization varies markedly in different normal human tissues. More to the point, these patterns are different when these tissues are infected or diseased. This reorganization of desmosomes is most evident in certain cancers (e.g., pulmonary squamous cell carcinoma). Alterations in desmosomes also underlie various skin disorders. For example, pemphigus vulgaris is an autoimmune disorder causing painful sores and blisters on the skin and in the mouth. It has been shown that sufferers produce antibodies against desmoglein 1 and 3. The presence of these antibodies interferes with the formation and maintenance of desmosomes which are central to the integrity of epithelial layers. The result is a breakdown in the skin. This ailment can also show up in people treated with certain medications such as certain heart drugs (e.g., acetylcholinesterase inhibitors). Other skin disorders are also being found to show desmosomal disruption.
As with other intercellular junctions, the formation and breakdown of desmosomes has other implications to cells especially in signal transduction events that can regulate gene activity. The reason for this is that when proteins are freed from their proper locations, they are then available to do some of the other jobs they might also hold. As detailed above, this can be bad when too much of a specific protein is released by tissue damage or disease. Now let’s move on to discuss some of the specific proteins we’ve mentioned to understand more about how they function and play roles in human infections and diseases.
Chapter 4
Gap Junctions: Communication in the Heart and Glands
The normal functioning of the human body involves a vast diversity of communication events that are occurring simultaneously at the cell and tissue level in every organ of your body every millisecond of every day. As we will see in this chapter and those to follow, the disruption of any one of these signaling events can lead to a debilitating disease. After we summarize the types of intercellular signaling, we’ll detail the specialized intercellular structure called the gap junction that is essential to the functioning of a diversity of tissues and organs in the human body.
We can define three types of intercellular signaling in the human body (Figure 4.1):
•Endocrine. Cells in one part of the body send hormones via the bloodstream to influence other parts.
•Paracrine. Cells secrete substances that influence other cells around them.
•Autocrine. Cells secrete substances that influence themselves.
Figure 4.1. Types of signaling that occur between cells in the human body.
Thus these types of intercellular communications are defined by the distance between the signaling cell and its target cell. Intercellular signaling can also be classified based upon the way in which the signaling molecules from one cell type impact the target cells. These are called modes of intercellular communication. In spite of the complexity of the human body and the diversity of intercellular communications that occur, the modes of cellular communication can be classified into four major groups.
Four Types of Intercellular Communication:
•Diffusible Molecules (e.g., hormones, growth factors, neurotransmitters)
•Cellular Continuities (e.g., gap junctions)
•Cell Contact (e.g., adhesion molecule and its receptor)
•Mediated by the Extracellular Matrix (e.g., fibronectin, laminin).
Gap Junctions
Gap junctions are more accurately considered to be communicating junctions rather than cell adhesion junctions. But their structure likely results in both functions. Gap junctions have many important functions in cells. In the brain, gap junctions allow direct signaling between neurons, between glial cells and between neurons and glial cells. Gap junctions are also known to appear at specific times to mediate certain events. For example, gap junctions appear in the myometrium of the uterus during the later stages of pregnancy so that uterine contractions can be precisely controlled during childbirth. During embryonic development, gap junctions appear in developing muscle cells (myoblasts) to co-ordinate their fusion into future muscle fibers. This is covered in more detail in the chapter on biomembrane fusion.
Gap Junction Structure
The pictures below show the structure of gap junctions (Figure 4.2, 4.3). The first two panels in the image on the left of Figure 4.2, show how gap junctions appear in the transmission and scanning electron microscopes, respectively. The right-hand panel shows what purified gap junctional components look like.
