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THE ORIGINAL CELLULAR PHONE: HOW A NATION OF
COMMUNICATING CELLS KEEPS YOU HEALTHY!
James E. Trosko, Ph.D.
246 Natl. Food Safety Toxicology Center
Dept. Pediatrics and Human Development
Michigan State University
East Lansing, Michigan 48824
and
Randall J. Ruch, Ph.D.
Dept. of Pathology
Medical College of Ohio
Toledo, Ohio 43614
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The Healthy Body as a Nation of Communicating Cells:
The United States is a nation of almost 300 million individuals, of different sexes, ages,
ethnicity, religious beliefs, and political views. Our nation and its individuals are at their
best when they can freely exchange information with themselves, other nations and
individuals across various levels of organization. We communicate with others by oral
and written words (language), sounds, facial expressions, body language, touch, and
smell. Communication leads to understanding, and if the two parties share similar views,
to trust and cooperation whether at the national or the individual level. Communication
makes us more "healthy" nationally and individually. We become "unhealthy” when
there is either no communication or miscommunication, because these lead to
misunderstanding, mistrust, hatred, and violence. Whether it's two nations, such as the
U.S. and Iraq on the verge of war or a husband and wife on the verge of divorce,
miscommunication can result in misunderstanding and potentially disastrous
consequences.
Like a nation comprised of millions of people, our bodies are composed of many cells; in
fact, there are approximately 100 trillion cells in the adult human body. Each cell starts
out genetically identical, yet ends up unique and organized into subgroups of similar cells
(tissues) that perform the necessary functions for the maintenance of the whole body.
Like a nation of individuals, communication between cells is necessary for the body to
function properly and remain healthy.
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The fertilized egg contains the genetic material from our mother and father via the sperm
and egg and gives rise to all of the cells in the adult body. Each of these cells contains a
unique set of approximately 30,000 genes that make up the human genome. The set of
genes each of us inherited from our parents is the foundation on which our cells respond
to various environmental factors and pyscho-social experiences (diet, medications,
pollutants, temperature, stress, etc.). The normal process of human development and
aging occurs when the fertilized egg develops in the uterus into a healthy embryo that
further develops into a viable fetus that is born and matures into a healthy child, adult,
and elderly geriatric. Throughout this process, the cells of the developing and maturing
individual, each with the unique set of inherited genes, must respond and adapt to its
environment, multiply, repair damage, sometimes die, and specialize (differentiate) into
all the cells needed for all the tasks of the body. This process is highly organized and
absolutely dependent upon cell-cell communication. Similar to a nation of individuals, in
the absence of cell-cell communication, "unhealthiness" or disease occurs (birth defects,
cancer, diabetes, deafness, infertility, nerve damage, etc.).
Within the embryo, however, some cells are set aside to provide more cells later in life
when other cells wear out, are injured, or are altered by disease. These cells are known as
“stem” cells and have the capacity for limitless regeneration. One excellent example is
the stem cells of the blood forming system. These cells replace old and damaged blood
cells on a continual basis or respond to stimuli (e.g., infections) by producing more cells.
But there are a variety of other types of stem cells in our body. Scientists are discovering
that these cells may replace old and damaged cells in all of the organs of our body such as
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the brain, heart, pancreas, and liver. When stem cells divide, one of the new daughter
cells becomes highly specialized or "differentiated" to perform the necessary functions of
the organ (for example, neurons in the brain and insulin-producing cells in the pancreas)
whereas the other daughter cell remains undifferentiated and continues as a stem cell.
Try to picture what is happening after the egg is fertilized and implanted in the uterus.
The fertilized egg divides to make two, four, eight, sixteen cells, etc. These cells form a
ball of cells that have the same genes and do pretty much the same thing. Then
something triggers these undifferentiated cells to specialize and develop into an embryo.
They do so by following a highly complicated set of "rules" that depend upon cell-cell
interactions and communication. As the embryo further develops into a fetus, groups of
cells form "micro-environments" or clusters of communicating cells that further develop
into the various organs. This involves highly scripted proliferation, death, and
differentiation of the cells and is carried out by the activation of new genes and the
inactivation of others. These processes - cell birth, death, and differentiation - occur over
and over on a grand scale during embryonic development with the result being, if all goes
well, a healthy fetus ready to be born. The development of any organism from a single
cell into a multi-cellular one, whether it is a primitive form such as a sponge, or a highly
evolved one such as a human being, is poorly understood. How is this delicate
orchestration of cell proliferation, differentiation, and death brought about?
Biological Cellular Communication: Humans today use much more sophisticated
means to communicate than did their ancestors. It was only a few centuries ago that the
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only means of communication was by the spoken and written word, body language,
drumbeats, smoke signals, and occasionally an accurately thrown rock or blow from a
club. Today we have much more sophisticated ways to exchange information with
people all over the planet and in outer space, and take these technologies for granted.
Wired and wireless phones, radios and walkie-talkies, television and video, paper and
electronic mail, and pagers and instant messaging enable us to "stay in touch" with others
and to exchange information and ideas in a rapid and sometimes seamless (or sometimes
senseless) manner.
But within our bodies, the 100 trillion cells are much better at communication. Our cells
are constantly sending and receiving information of all sorts using methods that make the
most sophisticated super-computer look like an abacus. As you read this, your eyes are
seeing the words, converting and sending the information via nerves to your brain,
processing and storing it there, and evoking a (hopefully positive) emotional response. In
the background, your muscles are telling you to get up and stretch, your heart is beating
smoothly, your temperature is tightly regulated, your breathing is neither too fast nor too
slow, and your digestive track has sensed your last meal and is breaking it down. All the
100 trillion cells of your body are receiving chemical and ionic messages, nutrients, and
oxygen and releasing useful molecules and waste products. They are quietly doing the
jobs their unique pattern of expressed genes has programmed them to do.
The number of cells in our healthy bodies is also tightly controlled because cell births and
deaths are in balance. This occurs with such precision that a Mercedes Benz engineer
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would be astounded. As you turn the page, dead skin cells are sloughed off on the paper
and are replaced by new cells that are the offspring of stem cells lining the base of the
skin. These new cells are pushed out to the surface of the skin by the continuous division
of the stem cells. As the cells move upward, they differentiate into layers of flat, tough,
waterproofing cells that provides a protective covering over our bodies that keeps
moisture in and bad things out.
These elegant processes are highly dependent upon complex cell-cell communication
systems that have evolved over millions of years. Cell-cell communication can be
subdivided into three types, extra-, intra-, and gap junctional intercellular
communication. Our cells are constantly releasing ions and molecules (growth factors,
neurotransmitters, hormones, etc.) that are "sensed" by close-by or neighboring cells or
that are released and carried by the blood to cells farther away. This is known as
extracellular communication. Usually "antennas" or receptors on the outside of a cell
detect these chemical signals, although some molecules can be detected without a
receptor. In either case, the detection of these molecular signals activates a cascade of
informative signals inside the cell (intracellular communication) that cause the cell to
modify its activity (adapt), change its function (differentiate), divide, or die.
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Many Forms of Cell-Cell “Communication” Regulate Tissue Function and Phenotype
ProgenitorCells
Substrate
Terminally-differentiated cell
Gap Junctions
Stem cell
Figure 1. This cartoon illustrates how three different kinds of cells within a tissue, the
stem cell, progenitor cells coupled by gap junction channels and the terminally-
differentiated cell communicate with each other. The stem cell communicates through the
extra-cellular substrate which triggers intra-cellular signals inside the cell. It is touching
its progenitor daughter cell via cell adhesion molecules. The progenitor cell receives
communication signals from both the cell adhesion molecules and the extra-cellular
substrate. All progenitor cells also communicate intra-cellular signals to their sister
progenitor cells via the gap junction intercellular channels. As a result, the progenitor
cells secrete extra-cellular communication molecules that can enter the blood stream to
communicate with distal cells that have receptors for those specific communication
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molecules (e.g., hormones, growth factor)( ) The progenitor cell can also
communicate with its terminally differentiated daughter cell via gap junctions Lastly, the
terminally differentiated cell, by also receiving signals from the extra-cellular substrate,
together with the gap junctional-intercellular communication signal, can secrete a
negative communicating signal back to the original stem cell ( ).
Overlying both extracellular and intracellular communication is a third form of cell-cell
communication, known as gap junctional intercellular communication. This type of
communication enables cells to exchange molecular and ionic signals directly through
tiny tunnels or passageways known as gap junctions that connect the interiors of
neighboring cells and, as we shall see, integrate a cell's response with other cells. (Figures
1 and 2).
Gap Junctions in Cellular Homeostasis
ToxicChemicals
receptorTranslational Regulators
Transcriptional RegulatorsPost translational Regulators
Biological End Points
Cellproliferation
CellDifferentiation
ApoptosisAdaptive responses ofdifferentiated cells
ExtracellularCommunication
IntracellularCommunication
Intercellular Communication
8
8
8 88
Growthfactor
Distal cell
is
= intercellular signal
Senescence
8
8
8 88
is
8
FIGURE 2. This cartoon tries to depict a general picture of how 100 trillion cells of the
body communicate with each other. The three cells illustrate two gap junctionally-
coupled cells in a tissue communicating with a cell from a distant tissue communicating
via an extra-cellular secreted molecule (e.g., hormones, growth factors). The extra-cellar
signaling molecules can trigger various intra-cellular signals in the target cell. These
intra-cellular signals can then be transferred to the neighboring cell via gap junctions.
Depending on the extra-cellular communicating molecule, the intra-cellular
communicating molecules can either increase or decrease the cells ability to transfer the
signals via gap junctions to its neighboring cell. As a result of either increased or
decreased gap junctional intercellular communication, the cell will either proliferate,
senesce, terminally differentiate or die of a programmed cell death ( “apoptosis”).
What is a Gap Junction and What Good is it?
Our bodies are not simply “skin-covered bags” filled with 100 trillion cells all sloshing
around like a water balloon. Our bodies have structure and the cells are held together and
organized into tissues; in turn, groups of tissues make-up organs. For example, the brain
contains many different kinds of neural cells, supportive (glial) cells, blood vessel cells,
and other cells. The liver contains hepatocytes, bile ductal cells, Kupffer cells, blood
cells, and others. The lungs are made up of over thirty different types of cells. Our
bodies have a structure or shape because the cells are attached to each other and to our
skeletons by several kinds of connections or cell-cell junctions. These junctions hold
cells together, form barriers to other cells and molecules, and in some cases, act as
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sensors that detect things outside the cell including other cells. Gap junctions are also a
type of cell-cell junction, but they are unique because they have pores or channels that
connect the insides of neighboring cells; other junctions do not have channels. (Figure 3).
FIGURE 3. This cartoon illustrates a gap junction. “Hemi-channels” or connexons,
consisting of six proteins called connexins that are coded by an evolutionarily-conserved
family of genes. When two hemichannels or connexons unite across the extra-cellular
space between two neighboring cells, they form a complete channel that allows ions and
small molecules from one cell to be transferred directly to the neighboring cell without
having to enter extra-cellular space.
The diameters of gap junction channels are very, very small - approximately 1.5-2
nanometers which is about 1/250,000 the width of the period at the end of this sentence.
Each channel is made from two hemi-channels or connexons. Proteins known as
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connexins form the connexons; each one contains six connexins so there are twelve
connexins in one complete channel. The human genome contains genes for
approximately twenty different kinds of connexins, so there are many potential building
blocks and combinations of connexins that cells can use to make gap junction channels.
But our cells usually express no more than three kinds of connexins. As will be
discussed below, however, this diversity enables cells to make a variety of channels with
unique properties.
Gap junction channels are so tiny that only very small molecules and ions can pass
through them from cell to cell. For example, amino acids, water, simple sugars, and most
intracellular signal molecules freely move through gap junction channels, but larger
molecules such as proteins and fats cannot. The channels are formed by the end-to-end
attachment of two "half-channels" or connexons when cells are in close proximity. The
connexons on opposite cells are attracted to each other in some unknown way and
connect or "dock" tightly together. Once two connexons are docked properly, the
complete channel will open and ions and molecules can then freely move between the
neighboring cells. In most gap junctions, several complete channels cluster in one small
region resulting in a gap junction "plaque". (FIGURE 4).
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FIGURE 4. This electron micrograph depicts a portion of a coupled pair of cells in
which a cross-section of a “plaque” or island of hundreds of coupled connexons
aggregate to form a “ gap junction”. Each cell can have multiple numbers and sizes of
these gap junction plaques, depending on the physiological state of the tissue.
This cell-cell movement of ions and molecules through gap junction channels is known
as gap junctional intercellular communication (GJIC). It is very important for the health
of the cell and the organism. GJIC helps balance and maintain cellular levels of critical
ions and nutrients, helps to supply neighboring cells with building blocks for larger
molecules, and helps coordinate cellular activities. Within most tissues, several gap
junction plaques connect the cells and in turn each is comprised of hundreds to thousands
of channels. Thus, although they are tiny, there may be thousands of channels that
connect two cells and effectively, there is plenty of room for molecular flow between
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them. In cells that are well-connected by gap junctions, molecules and ions move very
quickly from cell to cell so that within tissues, groups of cells respond more like a
functional unit than individual cells. Thus, GJIC is the rapid, direct flow of molecular
and ionic information between cells and helps to integrate the activities of multi-cellular
tissues. (FIGURE 5).
Physiological Functions of Gap Junctions
Homeostasisbuffering/sharing of ions,nutrients, and water
Electrical couplinglow-resistance synapsesin neurons and muscle
Embryogenesistransfer of “morphogenic”factors amongst cells indevelopmental fields
Enhanced Tissue Responsetransfer of second messengers fromstimulated to unstimulated cells
Metabolic supportnutrient transfer toavascular tissues
Regulation of Cell Growthexchange of growth controllingsignals between neighboring cells
FIGURE 5. This figure illustrates a number of the physiological functions that gap
junctional intercellular communication plays during embryogenesis, development of the
fetus, neonate, sexual and adolescent maturation, and adult functions in both electrically-
coupled tissues (e.g., heart) or non-electrically-coupled tissues (e.g., liver).
In the context of the organism, GJIC has many important functions. It helps control the
rates of cell births and deaths so that tissue size and activity remain constant. GJIC also
helps trigger cellular differentiation. By passage of intracellular signal molecules from
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stimulated to non-stimulated cells, GJIC also increases the overall response of the tissue
to a stimulus. In addition, gap junctions are the electrical pathways that certain types of
connect muscle cells (e.g., the heart, uterus, and digestive tract) and some nervous tissue,
and, thus, are critical for normal heartbeat, birth, digestion, brain activity, and other
functions. Gap junctions are "shipping lanes" for nutrients and waste products in tissues
that are not well supplied with blood vessels such as the lens of the eye and hardened
bone. Gap junctions are also involved in numerous other important cellular functions.
Thus, when an individual inherits a mutated form of a connexin gene, the cells that
express that gene will be unable to form normal gap junction channels and disease may
result. Several human diseases are due to the inheritance of a mutant connexin gene.
These include forms of nerve degeneration, deafness, cataracts, cancer, birth defects, and
skin disorders. (FIGURE 6).
Diseases Associated with Defective Gap Junctions
Cardiac arhythmia
Peripheral neuropathy
Hereditary deafness
Cataracts
Infertility
Teratogenesis
Cancer
Dysfunctional labor
Diabetes
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Figure 6. This figure illustrates what might happen if gap junctional communication is
disrupted, either by genetic mutations in the genes that code for the connexin proteins or
by environmental chemicals that could modify the numbers or functions of gap junctions.
In summary, GJIC enables cells to rapidly share critical ions and molecules that are
needed to regulate whether the cell remains inactive, proliferates, differentiates, commits
cell suicide, or adapts in response to external signals. This form of intercellular
communication integrates cells within a tissue so that they work together. When gap
junctions are defective, disease may result.
The highly coordinated systems of extra-, intra-, and intercellular communication are
characteristic of all multicellular organisms including humans. But the sciences of extra-
cellular and intracellular communication have had a long history of research (the
disciplines of physiology and biochemistry, respectively), whereas that of GJIC is a
relatively new area of research. This is in spite of the fact that gap junctions are found in
nearly all cells of the human body and throughout the animal kingdom including the most
primitive organisms such as sponges and jellyfish. In fact, gap junctions have been
around since multicellular organisms evolved from unicellular ones. Thus, gap junctions
are truly, "the original cellular phone."
CELLULAR PHONE NUMBERS: Now there might seem to be a problem with this
analogy between telephones and biological cellular phones. When humans call someone,
they dial a unique phone number for that person and in turn, each person in the USA has
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their own personalized phone number (sometimes more than one). But our cells only
have about twenty potential cellular phone “numbers” (the connexins) for 100 trillion
cells in the body. How can the cells communicate in a specific way? Well, it turns out
many cells “share” the same phone number (same type of gap junction) as in the old days
when there were “party lines”. Other cells, by virtue of expressing more than one
connexin and making connexon hemi-channels that contain combination of connexins,
communicate only with cells that make similar connexons.
Therefore, as an example, hepatocytes within the liver can communicate with other
hepatocytes because they both express a connexin known as connexin32, but not with
bile ductal liver cells that express connexin43. But these two groups of cells can still
communicate using extracellular communication, such as secreted growth factors or
hormones. Things, however, get a bit more complicated because combinations of the
twenty connexins provide even more specific communication routes. If more than one
connexin is expressed in a cell, there is the potential for several types of six-membered
connexons to be made: those containing only one type or a mixture of two or more.
But does this diversity of channel types have any relevance? Absolutely! The biological
reason for these twenty different connexins is that the various types of channels have
unique characteristics. Some molecules and ions pass through one type of channel better
than another. The expression (activity) of the connexin genes and the formation,
opening, and stability of the channels are controlled or regulated in different ways.
Lastly, only certain types of connexons can form functional channels with other types of
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connexons on adjacent cells. Sometimes gap junctions are "party lines" that allow many
cells to communicate; at other times they are highly specific with only a few cells "on the
line".
In many organs, cells of one type can communicate with other types of cells. What might
be the point of this? Cells have five basic cell choices or fates. Some cells have the
capacity to proliferate. Other cells need to differentiate into a highly specialized cell.
Still others, once terminally differentiated such that they cannot divide, must be able to
perform their differentiated function(s) and adapt to changing conditions such as
pancreatic cells that produce insulin when blood sugar levels increase. Other cells in
solid tissues must commit to undergo "cell suicide" or “programmed cell death” such that
tissue modeling or replacement with new, healthy cells can occur. Lastly, some cells are
destined to senesce, that is, to become non-proliferating, low activity, end-stage cells.
GJIC has been implicated in the determination of all of these cell fates. For example, in
the testes, developing sperm cells communicate by gap junctions with Sertoli cells. The
purpose of this is to trigger the differentiation process of the spermatocyte into a mature
sperm. The Sertoli cell is like a “nurse cell” and provides a molecular signal that triggers
the spermatocyte differentiation.
Disconnected Cellular Phones: Adaptive Response or Disease?
Gap junction-connected cells do not always stay that way. Sometimes, this is a normal,
biological process; other times, it is not. What happens when the biological cellular
phone is disconnected?
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Cells uncouple and re-couple with each other all the time as part of normal cellular
functions. Gap junction proteins are short-lived molecules and last only a few hours
before they are removed from the cell surface and digested inside the cell. As another
example, when cells are stimulated to divide by a growth factor, gap junction channels
close. Soon after the growth stimulus is received (extracellular signal), the cell must
"decide" (using intracellular signaling) whether to proliferate or remain quiet. To pursue
the first choice, the cell must disconnect its gap junctions so that it can disregard the
molecular signals or "influence" from neighboring cells that otherwise would keep the
stimulated cell inactive. Once the cell divides, the new daughter cells, if there is no more
growth stimulus, will form gap junctions with neighboring cells and "join the
community".
In other cases, gap junctions may be uncoupled at inappropriate times or the cells may be
incapable of forming functional gap junctions. The latter would be the case in cells that
harbor a mutant connexin gene. The former might be caused by factors generated inside
the body or might be due to outside agents that we are exposed to. If for any reason,
genetic, internal, or environmental - that GJIC is altered, serious consequences may occur
such as embryo lethality, birth defects, cancer, etc. This is true when there is GJIC at the
wrong time and place or when GJIC is deficient.
It was mentioned that there are now 20 known connexin genes. They are needed to
provide general and unique functions to all the hundreds of cell types and functions of the
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human body. With the development of modern genetic techniques, mice can be produced
that have one or more of their connexin genes permanently inactivated (connexin "knock-
out” mice). When certain connexin genes were knocked out, the resulting embryo or
fetus died before birth. This suggests these connexins are critical for normal embryonic
or fetal development. When other connexin genes were knocked-out, embryonic and
fetal development occurred normally. But shortly after birth, the mice died because of
defects in the organs in which the knocked-out connexins should have been expressed.
Finally, when other connexin genes were knocked out, the mice survived to adulthood,
but then developed diseases such as peripheral neuropathy, liver cancer, and cataracts.
In a manner similar to the "knockout" of a connexin gene or inheritance of a mutant
connexin, embryos or fetuses that are exposed to natural or synthetic chemicals, may
have their gap junctions altered (either increased or decreased inappropriately). This may
result in birth defects. Alcohol and thalidomide are two drugs that affect gap junctions
and cause birth defects.
Other chemical agents that are carcinogenic in animals alter gap junction formation and
function in cell- and connexin-specific ways. These include natural chemicals such as
the oil of the Croton plant; pollutants such as polybrominated biphenyls; drugs such as
phenobarbital; nutrients, such as unsaturated fatty acids, retinoids, and carotenoids;
pesticides such as DDT; metals such as cadmium; hormones such as estrogens; and
growth factors such as epidermal growth factor. These agents inhibit or enhance gap
junction formation or function, depending on the type and state of the cell and the
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connexin expressed. This effect may contribute to alterations of cell proliferation, cell
suicide, and cell differentiation and the development of diseases such as cancer.
Chemical alterations of GJIC in adult organisms may contribute to other diseases as well
(Figure 7).
Chemicals that inhibit gap junction function in the nervous system could be
neurotoxins. Other chemicals that inhibit gap junction function in the testes or ovary
could be reproductive toxicants. Still others that affect gap junctions in the immune
system could lead to decreased immunity. Gap junctions in the lens of the eye are
necessary for lens cells to receive nutrients and remove wastes and inhibition of this GJIC
may contribute to cataract formation.
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Figure 7. This panel of photographs illustrates an assay to detect whether cells are
communicating with each other via gap junctions. The lower right panel is a phase
micrograph of normal rat liver cells through which a razor blade cut a path through a
layer of cells grown in a plastic dish and not exposed to the fluorescent dye. The panel at
the top left shows that cells, which were not treated with any chemical (in this case, TPA,
a powerful skin tumor promoter) could transfer a fluorescent dye molecule which entered
the membranes of cells along the cut edge. Once in the cell, the fluorescent dye was
transferred to the neighboring cells via gap junctions. In a period of 5 minutes, the dye
went from the cut edge cells to about 10 cells away from the edge. This demonstrates that
the control normal rat liver cells could communicate well. In the subsequent panels
labeled with increasing concentrations of TPA, one sees a dramatic dose response
reduction in the cells ability to transfer the fluorescent dye from the cells along the cut
edge. This demonstrates that TPA, a known toxicant, could inhibit gap junctional
intercellular communication in a threshold, but dose- dependent fashion.
These examples do not prove in a strict scientific manner that chemical alteration
of gap junctions is the causative factor of a disease (“correlation does not mean
causation”). But since several known human diseases are due to the inheritance of a
mutant connexin gene, it is very likely that chemical alteration of GJIC contributes to
noninherited forms of these and other diseases.
An Evolutionary Perspective of Biological Cellular Communication
To put cell-cell communication in perspective, especially as it relates to maintaining
normal development, maturation and health, one can gain much by the insights that
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evolutionary theory provides. Clearly, a single bacterium is a living cell. This bacterium
can, indeed, communicate with its neighbors by the secreted molecules that enter the
medium in which it resides. It also has the means to communicate changes in the
environment to its internal cellular machinery. In other words it has the capacity for
extracellular and intracellular communication. This single cell organism survives
changes in its environment by its ability to proliferate and within its community of other
bacteria, it will continue to proliferate until either physical (temperature) or chemical
(nutrients) restrictions cause it to cease. Since the bacterium does not terminally
differentiate, it is essentially an “immortal” cell. If the environment puts real life-
threatening restrictions on this community of single cells, a bacterium that happened to
acquire a spontaneous or induced mutation in a critical gene that enabled their survival
would be the progenitor of the new bacterial community.
Early in the evolution of multicellular organisms from unicellular ones, the acquisition of
new survival traits had to occur. The early multicellular organism was probably a loose
collection of very similar cells. To evolve further, it had to develop means to control cell
proliferation, cell differentiation into various types of specialized cells, and cellular
suicide when cells were no longer needed or were damaged. The multicellular organism
also needed to keep on hand stem cells to replace old cells, and to produce gametes (eggs
and sperm) for reproductive success and continuation of the species.
But there was a “Faustian price” to pay for these new adaptive survival traits of multi-
cellular organisms. That price was a limited lifespan. The bacterium can be conceived of
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as immortal because if it has no internal restrictions on growth; it divides indefinitely to
produce other bacteria like itself. By becoming multicellular, however, the lifespan of
the organism became finite or “mortal”.
The point might be better illustrated by comparing a cancer cell to a single cell bacterium.
The cells of normal multicellular organisms have growth control, differentiate, undergo
cellular suicide, and have GJIC. The bacterium has no intrinsic growth control, cannot
terminally differentiate, is “immortal”, and lacks GJIC. More like a bacterium, cancer
cells lack growth control, do not terminally differentiate, are immortal, and lack normal
GJIC. Could the cancer cell be perceived as “reverting” back to an evolutionary stage of
the single bacterium? It is interesting to remember that a human being can become sick
and die from an uncontrolled bacterial infection (septicemia) or from an uncontrolled
“infection” of cancer cells (metastasis).
The transition from single cell organisms to multicellular ones required new genes for
intercellular communication in addition to those necessary for extra- and intracellular
communication. Arguably, the evolutionary invention of connexin genes and gap
junctions in the primitive multicellular organism could be viewed as one of the most
important steps in the transition from unicellular to multicellular life.
Preventing the Disconnection of Our Biological Cellular Phones
If one assumes that GJIC plays fundamental and critical roles in development, cell
proliferation, differentiation, etc., and that alteration of GJIC leads to diseases and other
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negative effects on the organism, it would be important to identify agents that restore
normal GJIC in affected tissues. In the laboratory, many chemicals have been identified
that prevent other chemicals from altering GJIC or that increase GJIC in cells with low
levels. These "good" chemicals block the effects of inhibitory chemicals and/or increase
the expression of connexin genes and formation of gap junctions. (Figure 8).
Vehicle Dicumyl-peroxide
Resveratrol + Dicumylperoxide
Effect of resveratrol on peroxide-induced inhibition of GJIC
FIGURE 8. These photographs, using the in vitro assay to measure gap junctional
intercellular communication, illustrate how a chemical, resveratrol, found in grape skins
and red wine, can prevent the inhibitory effect on GJIC by a tumor promoter,
dicumylperoxide. The panel at the top left illustrates that normal rat liver cells can
transfer a fluorescent dye which entered the scraped cells along the cut edge of a layer of
cells. Within 5 minutes the dye transferred from those cells to about 10 cells away from
the cut edge. This illustrates that normal rat liver cells, treated only with a non-toxic
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solvent ( “vehicle”) can communicate very well via gap junctions. The top right panel
shows that these cells, treated with non-cytotoxic concentrations of a tumor promoter,
dicumylperoxide, completely inhibited the transfer of the fluorescent dye. The bottom
panel demonstrates that the cells treated with both dicumylperoxide and resveratrol,had
higher levels of GJIC than cells treated only with dicumylperoxide. This suggests that
resveratrol could be a cancer chemo-preventive agent.
The task today is to identify the mechanisms by which disease-causing agents alter GJIC
and ways to prevent or correct that. There likely will never be a single “silver bullet”
since multiple agents and processes are involved. But published research data indicate
that agents that prevent or reverse negative effects on GJIC can prevent or reverse
disease. Clearly, however, this field is in its infancy and more research is necessary. But
its likely that in the near future, connecting and disconnecting our cellular phones will be
viewed as important tools to improve human health.
References:
J.E. Trosko and R. J. Ruch, “ Role of cell to cell communication in carcinogenesis”.
Frontiers in Bioscience 3: 208-236, 1998.
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