11.4Intercellular Communication

Through cell adhesion, cells communicate with others and receive signals from the outside. This section discusses the mechanisms and specific examples.

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Cell Adhesion and Intracellular Signaling

Many cell adhesion molecules penetrate plasma membranes, including cadherins and integrins. They play an important role in transmiting extracellular signals, which are received by adhering to other cells and extracellular matrix components, into the cell. The intracellular domain of cell adhesion molecules is associated with a protein that transfers extracellular signals into the cell. As an example, the intracellular domain of a cadherin binds with a catenin (a protein that regulates gene expression), and that of an integrin binds with a focal adhesion kinase (FAK) (an enzyme that phosphorylates amino acids).
The mechanism of extracellular signals being transferred into a cell through cell adhesion is discussed here, using an integrin as an example. If the extracellular domain of an integrin adheres to a particular extracellular matrix component, the signal is transduced to the intracellular domain of the integrin, thus activating the focal adhesion kinase attached to the intracellular domain (Fig. 11-6). As a result, a protein in the intracellular signaling system (a signaling factor) - a target of FAK - is phosphorylated, thus passing the extracellular signal on to the intracellular signaling system. Consequently, the signal is transmited into the nucleus to initiate the expression of genes.

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Cell Recognition

Cells recognize the type and character of other cells by adhering to them. As an example, through cell adhesion mediated by a cadherin, a cell recognizes whether the cell being adhered to is of the same type. A number of other mechanisms are also in place to identify the property of the cell being adhered to in further detail. One is the recognition of sugar chains located on the surface of the cell. Since sugar chains on the cell surface reflect a cell’s type and changes in its characteristics (e.g., changes exhibited by a cell that has turned cancerous, or differences in blood type), the character of the cell can be identified by recognizing the structural changes of sugar chains.

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Cell Adhesion and Locomotion

Since most of the cells that form the tissues and organs of the human body are firmly adhered to each other or to extracellular matrix, they cannot move freely. However, some cells, such as white blood cells, actively circulate throughout the body performing various roles on biological defense. During early development stage in animals, significant locomotion of germ cells is also observed within the whole embryo, and this plays an important role in forming the body structure (see Chapter 10).
Thus, cells inherently have migration activity. However, those that adhere to each other to form tissues and organs cannot move freely. Nevertheless, once the adhesion is unlocked and certain stimuli are applied, such cells initiate locomotive activity. Malignant cancer cells are an example of this; with their cell adhesion broken, they move freely around the body and multiply at their destinations, causing cancer metastasis.
Cell locomotion is regulated by many extracellular substances; especially diffusible chemoattractants and various adhesive molecules in extracellular matrix material play important roles. When these substances are bound to receptors on the plasma membrane such as integrins and receptors for chemoattractants, the signal is transmitted into the cell. As a result, various changes necessary for cell locomotion such as the degradation and reconstruction of the cytoskeleton, the contraction motion of the cell and the activation of intracellular substance transport, are induced, thus initiating cell locomotion (Fig. 11-7).

A model showing the steps of cell locomotion

Fig. 11-7. A model showing the steps of cell locomotion

a) A static cell attached to matrix material.
b) To initiate movement, the cell breaks the adhesion on the side of the direction of movement (right) and forms a protrusion in that direction.
c) The protrusion adheres to the matrix material, and the adhesion on the other side (left) is detached.
d) Lastly, the posterior part of the cell is contracted to push the cytoplasm forward, allowing the forward movement of the cell.

Cells may be engaged in directional movement. White blood cells moving toward an inflamed area (Fig. 11-8) and cells known as cellular slime molds moving toward their food - bacteria - are examples of this. In such cases, cells detect the concentration of chemoattractants diffused from the target and move toward it. This phenomenon is called chemotaxis, and the chemoattractants that cause it are called chemotactic factors. When this cellular behavior occurs, the chemoattractant receptors located on the plasma membrane play an important role.
Cells detect subtle changes in the concentration gradient of chemoattractants using their receptors, and the intracellular signaling pathway are activated. Cell protrusions are formed on the high-concentration side, and the formation of protrusions is suppressed on the opposite side. As a result, cellular locomotion toward the area of high chemoattractant concentration occurs (Fig. 11-9A).
Another example of directional cellular movement is the phenomenon observed when neuron protrusions extend toward sensory cells and muscle cells. Although nerves, sensory organs and muscle tissues form independently during the developmental process, they are subsequently connected by a functional network of nerve fibers. For this purpose, it is necessary for the tip of the nerve fiber (called growth cone) to extend toward the target cell and form synapse (Column Fig. 11-3) with it. For the nerve fiber to reach the target, a mechanism that accurately leads the extending tip is necessary. This mechanism is made possible by the receptors on the plasma membrane and the substances (ligands) that specifically bind to the receptors. Receptors bind to ligands may either extend protrusions toward an area with a high concentration of ligands or change the direction of the protrusions in a way that avoids the ligands (Fig. 11-9B). The extension direction of nerve fiber tips is regulated through these types of receptor.

Directional movement of a cell

Fig. 11-8. Directional movement of a cell

A chemotactism model of a white blood cell. White blood cells travel in blood vessels in a rolling motion while loosely adhering to the vascular endothelial cells. When a cell detects a chemoattractant (a chemotactic factor) released from an inflamed site during circulation, its adhesion to the endothelial cells becomes stronger. The cell then slips through the endothelial cells out of the vessel and migrates toward the area of higher chemoattractant concentration.

Concentration gradient of chemoattractants and chemotaxis

Fig. 11-9. Concentration gradient of chemoattractants and chemotaxis

A) A model of a cell being attracted by and moving toward chemoattractants. (1) The cell is exposed to the concentration gradient of the chemoattractants. (2) The chemoattractants bind to the receptors located on the plasma membrane on the high-concentration side at a high frequency. (3) As a result, cell protrusions are formed on the high-concentration side, while, the formation of protrusions is suppressed and cell contraction is induced on the opposite side. Through these steps, the cell moves toward the high-concentration area.
B) An extension model of neuron protrusions (growth cones). The extension direction of the growth cones moving toward the target is regulated by attractants or repulsion substances, such as diffusible chemicals and extracellular matrix components. Arrows indicate the extension direction of the cell protrusions.

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Plasmodesma of Plant Cells

Unlike animal cells, plant cells are surrounded by a cell wall, meaning that they cannot adhere to each other in the same manner as animal cells. However, plant cells still need to communicate with each other, and for this purpose they have a structure known as plasmodesma (Fig. 11-10). In a plasmodesma, the plasma membranes of adjacent cells are merged, forming tube-like structure with a diameter of 20 - 100 nm through which the cytoplasm and endoplasmic reticula are shared by the cells. Substances with a molecular weight of 800 or less can freely pass through the plasmodesmata by diffusion. However, a far greater molecules (such as certain proteins, RNA and viruses) are also known to pass through the plasmodesma. Special mechanisms may be involved in this phenomenon.
Plasmodesmata are similar to gap junctions in animal cells, in that cytoplasm is shared by two cells. The exchange of various substances through plasmodesmata allows intercellular communication.

Plasmodesma of plant cells

Fig. 11-10. Plasmodesma of plant cells

In plants, whose cells are surrounded by a cell wall, plasmodesmata are formed between adjacent cells, allowing them to share their cytoplasm. Endoplasmic reticula also pass through them between the cells.


Nerves and Synapses

An information network to respond to stimuli and to take action based on the consideration of various factors is formed in the human body. This is the nervous system, and is centered on the brain and the spinal cord. Junctions called synapses connect the neurons that constitute the system with other neurons and cells such as sensory cells, muscle cells and secretory cells. Synapses are specialized cell adhesion junctions that are necessary to efficiently transmit the excitation of sensory cells and neurons to other neurons and effectors (muscle cells and secretory cells).
Generally, cell excitation means changes in membrane potential. In other words, excitatory transmission by neurons means the transmission of changes in membrane potential to other cells via synapses. The two types of synapses are electrical synapses and chemical synapses (Column Fig. 11-3). Electrical synapses link two cells through gap junctions, which directly transmit changes in membrane potential between the cells. The transmission rate is therefore fast. On the other hand, chemical synapses indirectly transmit changes in membrane potential using chemical transmitters. For this reason, the transmission rate is relatively slow (although it still takes only milliseconds). In chemical synapses, a neuron on the excitement-transmitting side releases neurotransmitters such as adrenalin and acetylcholine, to the receiving cell. When these neurotransmitters bind to the receptors on the plasma membrane of the excitement-receiving cell, ion channels located on this plasma membrane open, causing changes in membrane potential of the receiving cell and allowing the transmission of the excitation.

Electrical and chemical synapses

Column Fig. 11-3. Electrical and chemical synapses

The excitatory transmission manner differs between electrical and chemical synapses. Electrical synapses transmit excitation directly through gap junctions, while chemical synapses transmit signals indirectly using chemical transmitters.


Junctional Complexes

Junctional complexes join epithelial cells together and consist of a number of adhesion types (Column Fig. 11-4). First, tight junctions tightly join the cells together. This type of junction encompasses the epithelial cells and forms a close association between them; the resulting gap is impermeable even to ions. Second, desmosomes are structures that physically and firmly connect epithelial cells. In this type of adhesion, the cells are firmly connected through the linking of cell adhesion molecules, which are in the same group of cadherins, to intracellular intermediate filaments. Third, there is a special cell adhesion mechanism called a gap junction, which is composed of two ion channels linked in series. Gap junctions serve as cytoplasm connection paths, through which ions and other small molecules freely move to the adjacent cell. Signaling molecules such as Ca2+ and cAMP can easily travel through gap junctions to mediate intercellular communication.
Other important cell adhesion mechanisms in epithelial tissues is hemidesmosome for binding the basal side of epithelial cells to basal laminae. Hemidesmosome is the connection of integrins and extracellular matrix. Epithelial cells are firmly connected to basal lamina by linking cell adhesion molecules to intermediate filaments, resembling desmosomes,

Junctional complexes that connect epithelial cells

Column Fig. 11-4. Junctional complexes that connect epithelial cells

Epithelial cells are connected by adhesion structures called junctional complexes, which consist of tight junctions, desmosomes and gap junctions on the lateral side. On the basal side, cells are adhered to basal laminae by hemidesmosomes.

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