| Cell Signalling |
Above: a gap junction in a cell-surface membrane, as seen from inside the cell.
Cell signaling (cell signalling, cellular signaling) is a general term for communication between cells and within
cells. In a multicellular organism, the cells must be robustly regulated and integrated and to achieve this
cells must often send instructions or signals to one-another. The billions of cells in the body of a vertebrate,
such as a human, must communicate, directly or indirectly, if they are to grow and develop in a coordinated
manner. Damage or impairment to a cell's communication apparatus (such as by radiation, toxic chemicals
or by virus takeover) often results in non-useful anomalous growth, as tumours or cancers. Cell signaling is
extremely complex and it is currently one of the most active areas of front-line research.
Electrical Signalling
One of the most important and basic modes of communication is by direct contact. Cells induced to grow in
culture, or during wound healing, keep growing and dividing by mitosis (see cell cycle) until they are
surrounded by neighbouring cells. Consider epithelial cells. The term 'epithelium' is defined differently by
different groups of scientists, but properly refers to a covering tissue, comprising one or more layers of
epithelial cells that cover an external or internal surface of an organ or organism. By this definition, the skin,
the lining of the gut lumen and the lining of the lumen of a blood vessel are all epithelium. An internal
covering such as the lining of a blood vessel is also called endothelium. Epithelium is essentially a 2D tissue.
The cells in healing skin, for example, will stop dividing once they make contact with cells around their whole
perimeter and then stop. This process is known as contact inhibition. It occurs because each cell senses
the presence of its neighbours - that is because the cells communicate with other cells in contact with them.
If contact inhibition fails, then a tumour may result - a mass of cells that keep growing.
Cells can pass signals during direct contact, when separated a short distance but connected via tissue fluid,
or when remote from one-another but connected by blood circulation. One of the mechanisms by which cells
communicate by direct contact is through membrane proteins - proteins on or embedded in the cell-surface
membrane. One example of this are gap junctions, which are found in animal cells. These occur in regions
where the cell membranes of two neighbouring cells are in very close contact. these regions are called
gap-junction plaques. Protein channels, called connexons, are clustered in these regions. Each
connexon is made up of 6 connexin protein subunits and forms a small channel. The connexons of one cell
aline with and join to the connexons of the neighbouring cell. Each connexon completely crosses the cell
membrane, so that a channel or pore is formed which crosses from the cytosol of one cell straight into the
cytosol of another, as illustrated below:
Cell signaling (cell signalling, cellular signaling) is a general term for communication between cells and within
cells. In a multicellular organism, the cells must be robustly regulated and integrated and to achieve this
cells must often send instructions or signals to one-another. The billions of cells in the body of a vertebrate,
such as a human, must communicate, directly or indirectly, if they are to grow and develop in a coordinated
manner. Damage or impairment to a cell's communication apparatus (such as by radiation, toxic chemicals
or by virus takeover) often results in non-useful anomalous growth, as tumours or cancers. Cell signaling is
extremely complex and it is currently one of the most active areas of front-line research.
Electrical Signalling
One of the most important and basic modes of communication is by direct contact. Cells induced to grow in
culture, or during wound healing, keep growing and dividing by mitosis (see cell cycle) until they are
surrounded by neighbouring cells. Consider epithelial cells. The term 'epithelium' is defined differently by
different groups of scientists, but properly refers to a covering tissue, comprising one or more layers of
epithelial cells that cover an external or internal surface of an organ or organism. By this definition, the skin,
the lining of the gut lumen and the lining of the lumen of a blood vessel are all epithelium. An internal
covering such as the lining of a blood vessel is also called endothelium. Epithelium is essentially a 2D tissue.
The cells in healing skin, for example, will stop dividing once they make contact with cells around their whole
perimeter and then stop. This process is known as contact inhibition. It occurs because each cell senses
the presence of its neighbours - that is because the cells communicate with other cells in contact with them.
If contact inhibition fails, then a tumour may result - a mass of cells that keep growing.
Cells can pass signals during direct contact, when separated a short distance but connected via tissue fluid,
or when remote from one-another but connected by blood circulation. One of the mechanisms by which cells
communicate by direct contact is through membrane proteins - proteins on or embedded in the cell-surface
membrane. One example of this are gap junctions, which are found in animal cells. These occur in regions
where the cell membranes of two neighbouring cells are in very close contact. these regions are called
gap-junction plaques. Protein channels, called connexons, are clustered in these regions. Each
connexon is made up of 6 connexin protein subunits and forms a small channel. The connexons of one cell
aline with and join to the connexons of the neighbouring cell. Each connexon completely crosses the cell
membrane, so that a channel or pore is formed which crosses from the cytosol of one cell straight into the
cytosol of another, as illustrated below:
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These connexon-tubes allow small molecules and ions to pass from cell to cell. The channels are minute,
with a pore diameter of about 1.2 to 2 nm (nm, nanometre = 1 billionth or 10E-9 of a millimetre). From less
than a dozen to over one thousand channels may exist in a single plaque, which may several nm or several
micrometres in diameter. The individual channels can be opened or closed, in response to appropriate
signals, allowing the cell to control the passage of materials through them. One of the substances
commonly transported through these channels is calcium, as calcium ions, Ca2+. These ions are major
cell-signalling molecules and may be released by a cell in response to a wide-range of stimuli, from touch
to hormonal stimulation. Calcium ions act as a second messenger, the original stimulus being the first
messenger, such as a hormone molecule delivered in the bloodstream.
Waves and spikes of calcium ions are released into the cytosol (some come from the extracellular fluid,
some from internal stores in specialised regions of the endoplasmic reticulum). These waves constitute an
intracellular message, relaying signals from one part of a cell to another. The diffusion of calcium ions into
another part of the cytoplasm triggers the release of more calcium into the cytosol, so the waves become
self-propagating. Since calcium ions can cross open gap junctions these waves may pass from one cell
into neighbouring cells. Calcium ions, despite being vital messengers, are also toxic to cells when in high
concentration and the calcium ions are quickly removed from the cytosol, being pumped back into their
stores in the endoplasmic reticulum or expelled from the cell (the mitochondria also take-up any excess
calcium) and the waves dampen down and disappear. Typically, the stimulus will spread across several
cells before dying down.
When cells die, they lose their ability to regulate calcium and calcium ions flood into the cell. To prevent
this from causing damage, or firing false-signals in neighbouring cells, the gap junctions close to isolate
dead and dying cells.
Since calcium and other ions that cross gap junctions carry electric charge, the gap junctions are
essentially acting as electrical synapses, electrically coupling the cells together into a sensitive network. In
bone the star-shaped osteblasts are connected by gap junctions at the tips of their many ray-like
processes, so that the whole bone is permeated by a living network of electrically-connected cells which
form a sensory network, responding to pressures placed upon the bone by producing calcium wave signals
which trigger cell activity, causing the bone to be remodeled according to requirements. In heart muscle,
the heart muscle cells are connected by gap junctions (at the intercalated discs) and these are thought to
play a role in synchronising the heart muscle by passing signals from cell to cell (possibly involving sodium
ions crossing the junctions, though other mechanisms are possibly involved). Gap junctions also form
electrical synapses between certain nerve cells (neurons) in some neural circuits in which speed, but not
directionality, is most important. (The nervous system makes extensive use of another type of synapse,
called the electrochemical synapse). Gap junctions occur in many tissues and have important functions in
synchronising the activity of the cells.
Similar junctions (though not called gap junctions and differing in structure) occur in plant cells
(plasmodesmata), fungi, algae and some prokaryotes (such as in chains of cyanobacterial cells in which
pores allow the passage of hydrogen ions between cells, synchronising the direction of gliding motility).
Chemical Signalling
Pre-requisites: cell membranes, cell nucleus
Cells within the same tissue or organ may secrete chemical messengers - molecules that diffuse through
the tissue fluid to other cells in the tissue. If these cells have the appropriate messenger sensor or receptor
(a protein or glycoprotein in the cell-surface membrane) and a molecule of the messenger binds to one of
these receptors then the target cell will detect the signal and respond. This allows for communication over
greater distances than gap junctions. An extension of this method involves water-soluble hormones,
carried in the blood stream to the tissues where they enter the tissue fluid and bind to receptors on the
target cells in the target organs. Hormones travel throughout the body, but only those target cells with the
right receptor can respond to the signal (rather like radio waves may travel throughout a city but only those
radios tuned in to the right frequency can respond). A good example is the hormone insulin. Insulin is a
small peptide (a chain of amino acids) that is secreted into the bloodstream by beta cells in the pancreas,
whenever blood sugar (glucose) levels rise, such as after a meal. Insulin travels around the body in the
bloodstream until it reaches target cells in the liver, skeletal muscles and fat cells (adipose tissue) where it
binds to a specific receptor glycoprotein on the surface of these cells. The receptor spans the cell-surface
membrane and binding of the hormone (acting as a ligand) causes a conformational (shape) change in the
receptor, switching on the secondary signal-generating part of the receptor in the cytosol, just inside the
membrane. This is illustrated below:
with a pore diameter of about 1.2 to 2 nm (nm, nanometre = 1 billionth or 10E-9 of a millimetre). From less
than a dozen to over one thousand channels may exist in a single plaque, which may several nm or several
micrometres in diameter. The individual channels can be opened or closed, in response to appropriate
signals, allowing the cell to control the passage of materials through them. One of the substances
commonly transported through these channels is calcium, as calcium ions, Ca2+. These ions are major
cell-signalling molecules and may be released by a cell in response to a wide-range of stimuli, from touch
to hormonal stimulation. Calcium ions act as a second messenger, the original stimulus being the first
messenger, such as a hormone molecule delivered in the bloodstream.
Waves and spikes of calcium ions are released into the cytosol (some come from the extracellular fluid,
some from internal stores in specialised regions of the endoplasmic reticulum). These waves constitute an
intracellular message, relaying signals from one part of a cell to another. The diffusion of calcium ions into
another part of the cytoplasm triggers the release of more calcium into the cytosol, so the waves become
self-propagating. Since calcium ions can cross open gap junctions these waves may pass from one cell
into neighbouring cells. Calcium ions, despite being vital messengers, are also toxic to cells when in high
concentration and the calcium ions are quickly removed from the cytosol, being pumped back into their
stores in the endoplasmic reticulum or expelled from the cell (the mitochondria also take-up any excess
calcium) and the waves dampen down and disappear. Typically, the stimulus will spread across several
cells before dying down.
When cells die, they lose their ability to regulate calcium and calcium ions flood into the cell. To prevent
this from causing damage, or firing false-signals in neighbouring cells, the gap junctions close to isolate
dead and dying cells.
Since calcium and other ions that cross gap junctions carry electric charge, the gap junctions are
essentially acting as electrical synapses, electrically coupling the cells together into a sensitive network. In
bone the star-shaped osteblasts are connected by gap junctions at the tips of their many ray-like
processes, so that the whole bone is permeated by a living network of electrically-connected cells which
form a sensory network, responding to pressures placed upon the bone by producing calcium wave signals
which trigger cell activity, causing the bone to be remodeled according to requirements. In heart muscle,
the heart muscle cells are connected by gap junctions (at the intercalated discs) and these are thought to
play a role in synchronising the heart muscle by passing signals from cell to cell (possibly involving sodium
ions crossing the junctions, though other mechanisms are possibly involved). Gap junctions also form
electrical synapses between certain nerve cells (neurons) in some neural circuits in which speed, but not
directionality, is most important. (The nervous system makes extensive use of another type of synapse,
called the electrochemical synapse). Gap junctions occur in many tissues and have important functions in
synchronising the activity of the cells.
Similar junctions (though not called gap junctions and differing in structure) occur in plant cells
(plasmodesmata), fungi, algae and some prokaryotes (such as in chains of cyanobacterial cells in which
pores allow the passage of hydrogen ions between cells, synchronising the direction of gliding motility).
Chemical Signalling
Pre-requisites: cell membranes, cell nucleus
Cells within the same tissue or organ may secrete chemical messengers - molecules that diffuse through
the tissue fluid to other cells in the tissue. If these cells have the appropriate messenger sensor or receptor
(a protein or glycoprotein in the cell-surface membrane) and a molecule of the messenger binds to one of
these receptors then the target cell will detect the signal and respond. This allows for communication over
greater distances than gap junctions. An extension of this method involves water-soluble hormones,
carried in the blood stream to the tissues where they enter the tissue fluid and bind to receptors on the
target cells in the target organs. Hormones travel throughout the body, but only those target cells with the
right receptor can respond to the signal (rather like radio waves may travel throughout a city but only those
radios tuned in to the right frequency can respond). A good example is the hormone insulin. Insulin is a
small peptide (a chain of amino acids) that is secreted into the bloodstream by beta cells in the pancreas,
whenever blood sugar (glucose) levels rise, such as after a meal. Insulin travels around the body in the
bloodstream until it reaches target cells in the liver, skeletal muscles and fat cells (adipose tissue) where it
binds to a specific receptor glycoprotein on the surface of these cells. The receptor spans the cell-surface
membrane and binding of the hormone (acting as a ligand) causes a conformational (shape) change in the
receptor, switching on the secondary signal-generating part of the receptor in the cytosol, just inside the
membrane. This is illustrated below:
The secondary signal is an intracellular signal (a signal within the target cell) which amplifies and relays the
signal to various parts of the cell, including the nucleus where certain genes are switched on to produce
necessary proteins for the cell to switch its activity to glucose absorption.
Thus insulin signals the target cells to take up glucose from the blood, lowering glucose levels.
The body regulates glucose level to a set-point, about which it gently oscillates. If glucose levels fall too
low, then a second hormone, glucagon, which is antagonistic to insulin (that is acts opposite to insulin) and
signals the liver to release glucose (from glycogen stores) into the bloodstream. Together, insulin and
glucagon form a feedback control circuit that regulates blood glucose levels. This is vital: if glucose levels
fall too low then cells, including brain cells, run out of fuel; if glucose levels rise too high then the blood
becomes hyperosmotic to the cells and water leaves the cells by osmosis, dehydrating them (see osmosis).
signal to various parts of the cell, including the nucleus where certain genes are switched on to produce
necessary proteins for the cell to switch its activity to glucose absorption.
Thus insulin signals the target cells to take up glucose from the blood, lowering glucose levels.
The body regulates glucose level to a set-point, about which it gently oscillates. If glucose levels fall too
low, then a second hormone, glucagon, which is antagonistic to insulin (that is acts opposite to insulin) and
signals the liver to release glucose (from glycogen stores) into the bloodstream. Together, insulin and
glucagon form a feedback control circuit that regulates blood glucose levels. This is vital: if glucose levels
fall too low then cells, including brain cells, run out of fuel; if glucose levels rise too high then the blood
becomes hyperosmotic to the cells and water leaves the cells by osmosis, dehydrating them (see osmosis).
Fat-soluble hormones, such as steroid hormones, generally operate by a different mechanism. Being fat
soluble they do not dissolve easily in blood and so are largely transported in the blood bound to specific
carrier proteins. When they arrive at their target cells, they are able to dissolve in the lipid-rich cell-surface
membrane and enter the cytosol by passive simple diffusion (see membranes and transport). They either
bind to specific protein receptors in the cytosol or in the nucleus of the cell. Testosterone binds to a
receptor in the cytosol and then the receptor-testosterone complex moves into the nucleus, where the
testosterone signals specific genes to switch on.
soluble they do not dissolve easily in blood and so are largely transported in the blood bound to specific
carrier proteins. When they arrive at their target cells, they are able to dissolve in the lipid-rich cell-surface
membrane and enter the cytosol by passive simple diffusion (see membranes and transport). They either
bind to specific protein receptors in the cytosol or in the nucleus of the cell. Testosterone binds to a
receptor in the cytosol and then the receptor-testosterone complex moves into the nucleus, where the
testosterone signals specific genes to switch on.
How is the secondary signal amplified and relayed to other parts of the cell?
This is a complex topic and only the basics and a few examples will be covered here. Let us begin with an
example.
Tyrosine receptor kinases (TRKs)
Serpentine (heptahelical) G-protein coupled receptors (GPCRs)
under construction ...
This is a complex topic and only the basics and a few examples will be covered here. Let us begin with an
example.
Tyrosine receptor kinases (TRKs)
Serpentine (heptahelical) G-protein coupled receptors (GPCRs)
under construction ...