![Chemotaxis1](https://upload.wikimedia.org/wikipedia/commons/2/23/Chemotaxis1.jpg)
Chemotaxis (from ''
chemo-'' + ''
taxis
A taxis (; ) is the movement of an organism in response to a stimulus such as light or the presence of food. Taxes are innate behavioural responses. A taxis differs from a tropism (turning response, often growth towards or away from a stim ...
'') is the movement of an organism or entity in response to a chemical stimulus.
Somatic cells,
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...
, and other
single-cell or
multicellular
A multicellular organism is an organism that consists of more than one cell, in contrast to unicellular organism.
All species of animals, land plants and most fungi are multicellular, as are many algae, whereas a few organisms are partially un ...
organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food (e.g.,
glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...
) by swimming toward the highest concentration of food molecules, or to flee from
poisons (e.g.,
phenol
Phenol (also called carbolic acid) is an aromatic organic compound with the molecular formula . It is a white crystalline solid that is volatile. The molecule consists of a phenyl group () bonded to a hydroxy group (). Mildly acidic, it ...
). In multicellular organisms, chemotaxis is critical to early development (e.g., movement of
sperm towards the egg during
fertilization
Fertilisation or fertilization (see spelling differences), also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give rise to a new individual organism or offspring and initiate its development. Proce ...
) and development (e.g., migration of
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
s or
lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
s) as well as in normal function and health (e.g., migration of
leukocytes
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
during injury or infection). In addition, it has been recognized that mechanisms that allow chemotaxis in animals can be subverted during
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
metastasis
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then ...
. The aberrant chemotaxis of leukocytes and lymphocytes also contribute to inflammatory diseases such as atherosclerosis, asthma, and arthritis. Sub-cellular components, such as the polarity patch generated by mating yeast, may also display chemotactic behavior.
''Positive'' chemotaxis occurs if the movement is toward a higher concentration of the chemical in question; ''negative'' chemotaxis if the movement is in the opposite direction. Chemically prompted
kinesis (randomly directed or nondirectional) can be called
chemokinesis Chemokinesis is chemically prompted kinesis, a motile response of unicellular prokaryotic or eukaryotic organisms to chemicals that cause the cell to make some kind of change in their migratory/swimming behaviour. Changes involve an increase or de ...
.
History of chemotaxis research
Although migration of cells was detected from the early days of the development of microscopy by
Leeuwenhoek, a Caltech lecture regarding chemotaxis propounds that 'erudite description of chemotaxis was only first made by
T. W. Engelmann (1881) and
W. F. Pfeffer (1884) in bacteria, and
H. S. Jennings (1906) in
ciliate
The ciliates are a group of alveolates characterized by the presence of hair-like organelles called cilia, which are identical in structure to eukaryotic flagella, but are in general shorter and present in much larger numbers, with a differen ...
s'. The Nobel Prize laureate
I. Metchnikoff also contributed to the study of the field during 1882 to 1886, with investigations of the process as an initial step of
phagocytosis
Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...
. The significance of chemotaxis in biology and clinical pathology was widely accepted in the 1930s, and the most fundamental definitions underlying the phenomenon were drafted by this time. The most important aspects in quality control of
chemotaxis assay
Chemotaxis assays are experimental tools for evaluation of chemotactic ability of prokaryotic or eukaryotic cells.
A wide variety of techniques have been developed. Some techniques are qualitative - allowing an investigator to approximately dete ...
s were described by
H. Harris in the 1950s. In the 1960s and 1970s, the revolution of modern cell biology and biochemistry provided a series of novel techniques that became available to investigate the migratory responder cells and subcellular fractions responsible for chemotactic activity.
The availability of this technology led to the discovery of C5a, a major chemotactic factor involved in acute inflammation. The pioneering works of
J. Adler modernized Pfeffer's capillary assay and represented a significant turning point in understanding the whole process of intracellular signal transduction of bacteria.
Bacterial chemotaxis—general characteristics
![ChtxCCW CW (Fixed)](https://upload.wikimedia.org/wikipedia/commons/2/2e/ChtxCCW_CW_%28Fixed%29.png)
Some
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...
, such as ''
E. coli'', have several
flagella per cell (4–10 typically). These can rotate in two ways:
# Counter-clockwise rotation aligns the flagella into a single rotating bundle, causing the bacterium to swim in a straight line; and
# Clockwise rotation breaks the flagella bundle apart such that each flagellum points in a different direction, causing the bacterium to tumble in place.
The directions of rotation are given for an observer outside the cell looking down the flagella toward the cell.
Behavior
The overall movement of a bacterium is the result of alternating tumble and swim phases, called
run-and-tumble motion
Run-and-tumble motion is a movement pattern exhibited by certain bacteria and other microscopic agents. It consists of an alternating sequence of "runs" and "tumbles": during a run, the agent propels itself in a fixed (or slowly varying) directio ...
. As a result, the trajectory of a bacterium swimming in a uniform environment will form a
random walk
In mathematics, a random walk is a random process that describes a path that consists of a succession of random steps on some mathematical space.
An elementary example of a random walk is the random walk on the integer number line \mathbb Z ...
with relatively straight swims interrupted by random tumbles that reorient the bacterium. Bacteria such as ''
E. coli'' are unable to choose the direction in which they swim, and are unable to swim in a straight line for more than a few seconds due to rotational
diffusion
Diffusion is the net movement of anything (for example, atoms, ions, molecules, energy) generally from a region of higher concentration to a region of lower concentration. Diffusion is driven by a gradient in Gibbs free energy or chemica ...
; in other words, bacteria "forget" the direction in which they are going. By repeatedly evaluating their course, and adjusting if they are moving in the wrong direction, bacteria can direct their random walk motion toward favorable locations.
In the presence of a chemical
gradient
In vector calculus, the gradient of a scalar-valued differentiable function of several variables is the vector field (or vector-valued function) \nabla f whose value at a point p is the "direction and rate of fastest increase". If the gr ...
bacteria will chemotax, or direct their overall motion based on the gradient. If the bacterium senses that it is moving in the correct direction (toward attractant/away from repellent), it will keep swimming in a straight line for a longer time before tumbling; however, if it is moving in the wrong direction, it will tumble sooner. Bacteria like ''
E. coli'' use temporal sensing to decide whether their situation is improving or not, and in this way, find the location with the highest concentration of attractant, detecting even small differences in concentration.
This biased random walk is a result of simply choosing between two methods of random movement; namely tumbling and straight swimming. The helical nature of the individual flagellar filament is critical for this movement to occur. The protein structure that makes up the flagellar filament,
flagellin
Flagellin is a globular protein that arranges itself in a hollow cylinder to form the filament in a bacterial flagellum. It has a mass of about 30,000 to 60,000 daltons. Flagellin is the principal component of bacterial flagella, and is present ...
, is conserved among all flagellated bacteria. Vertebrates seem to have taken advantage of this fact by possessing an immune receptor (
TLR5
Toll-like receptor 5, also known as TLR5, is a protein which in humans is encoded by the ''TLR5'' gene. It is a member of the toll-like receptor (TLR) family. TLR5 is known to recognize bacterial flagellin from invading mobile bacteria. It has bee ...
) designed to recognize this conserved protein.
As in many instances in biology, there are bacteria that do not follow this rule. Many bacteria, such as ''Vibrio'', are monoflagellated and have a single flagellum at one pole of the cell. Their method of chemotaxis is different. Others possess a single flagellum that is kept inside the cell wall. These bacteria move by spinning the whole cell, which is shaped like a corkscrew.
Signal transduction
Chemical gradients are sensed through multiple
transmembrane receptor
Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral me ...
s, called methyl-accepting chemotaxis proteins (MCPs), which vary in the molecules that they detect. Thousands of MCP receptors are known to be encoded across the bacterial kingdom. These receptors may bind attractants or repellents directly or indirectly through interaction with proteins of
periplasmatic space. The signals from these receptors are transmitted across the
plasma membrane into the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
, where ''
Che proteins
Che, Ché, Chè or CHE may refer to:
People
* Ché Ahn, (born 1956), American Christian pastor
* Che Guevara (1928–1967), Argentine Marxist revolutionary
* Che (surname) (车), Chinese surname
* Che Lovelace (born 1969), Trinidadian artist
Ar ...
'' are activated.
The Che proteins alter the tumbling frequency, and alter the receptors.
Flagellum regulation
The proteins CheW and CheA bind to the receptor. The absence of receptor activation results in
autophosphorylation
Autophosphorylation is a type of post-translational modification of proteins. It is generally defined as the phosphorylation of the kinase by itself. In eukaryotes, this process occurs by the addition of a phosphate group to serine, threoni ...
in the
histidine kinase
Histidine kinases (HK) are multifunctional, and in non-animal kingdoms, typically transmembrane, proteins of the transferase class of enzymes that play a role in signal transduction across the cellular membrane. The vast majority of HKs are hom ...
, CheA, at a single highly conserved histidine residue. CheA, in turn, transfers phosphoryl groups to conserved aspartate residues in the response regulators CheB and CheY; CheA is a histidine kinase and it does not actively transfer the phosphoryl group, rather, the response regulator
CheB
Cheb (; german: Eger) is a town in the Karlovy Vary Region of the Czech Republic. It has about 30,000 inhabitants. It lies on the river Ohře.
Before the 1945 expulsion of the German-speaking population, the town was the centre of the German-s ...
takes the phosphoryl group from CheA. This mechanism of signal transduction is called a
two-component system, and it is a common form of signal transduction in bacteria. CheY induces tumbling by interacting with the flagellar switch protein FliM, inducing a change from counter-clockwise to clockwise rotation of the flagellum. Change in the rotation state of a single flagellum can disrupt the entire flagella bundle and cause a tumble.
Receptor regulation
CheB, when activated by CheA, acts as a
methylesterase, removing methyl groups from
glutamate residues on the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
ic side of the receptor; it works antagonistically with CheR, a methyl
transferase
A transferase is any one of a class of enzymes that catalyse the transfer of specific functional groups (e.g. a methyl or glycosyl group) from one molecule (called the donor) to another (called the acceptor). They are involved in hundreds of ...
, which adds methyl residues to the same glutamate residues.
If the level of an attractant remains high, the level of phosphorylation of CheA (and, therefore, CheY and CheB) will remain low, the cell will swim smoothly, and the level of methylation of the MCPs will increase (because CheB-P is not present to demethylate).
The MCPs no longer respond to the attractant when they are fully methylated; therefore, even though the level of attractant might remain high, the level of CheA-P (and CheB-P) increases and the cell begins to tumble.
The MCPs can be demethylated by CheB-P, and, when this happens, the receptors can once again respond to attractants.
The situation is the opposite with regard to repellents: fully methylated MCPs respond best to repellents, while least-methylated MCPs respond worst to repellents. This regulation allows the bacterium to 'remember' chemical concentrations from the recent past, a few seconds, and compare them to those it is currently experiencing, thus 'know' whether it is traveling up or down a gradient.
that bacteria have to chemical gradients, other mechanisms are involved in increasing the absolute value of the sensitivity on a given background. Well-established examples are the ultra-sensitive response of the motor to the CheY-P signal, and the clustering of chemoreceptors.
Chemoattractants and chemorepellents
Chemoattractants and chemorepellents are
inorganic
In chemistry, an inorganic compound is typically a chemical compound that lacks carbon–hydrogen bonds, that is, a compound that is not an organic compound. The study of inorganic compounds is a subfield of chemistry known as ''inorganic chemist ...
or
organic substances possessing chemotaxis-inducer effect in motile cells. These chemotactic
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...
s create chemical concentration gradients that organisms, prokaryotic and eukaryotic, move toward or away from, respectively.
![Chtx-AttrRep-en](https://upload.wikimedia.org/wikipedia/commons/d/d8/Chtx-AttrRep-en.png)
Effects of chemoattractants are elicited via chemoreceptors such as
methyl-accepting chemotaxis proteins (MCP).
MCPs in E.coli include Tar, Tsr, Trg and Tap.
Chemoattracttants to Trg include
ribose
Ribose is a simple sugar and carbohydrate with molecular formula C5H10O5 and the linear-form composition H−(C=O)−(CHOH)4−H. The naturally-occurring form, , is a component of the ribonucleotides from which RNA is built, and so this compo ...
and
galactose
Galactose (, '' galacto-'' + ''-ose'', "milk sugar"), sometimes abbreviated Gal, is a monosaccharide sugar that is about as sweet as glucose, and about 65% as sweet as sucrose. It is an aldohexose and a C-4 epimer of glucose. A galactose molecu ...
with
phenol
Phenol (also called carbolic acid) is an aromatic organic compound with the molecular formula . It is a white crystalline solid that is volatile. The molecule consists of a phenyl group () bonded to a hydroxy group (). Mildly acidic, it ...
as a chemorepellent. Tap and Tsr recognize
dipeptide A dipeptide is an organic compound derived from two amino acids. The constituent amino acids can be the same or different. When different, two isomers of the dipeptide are possible, depending on the sequence. Several dipeptides are physiologicall ...
s and
serine as chemoattractants, respectively.
Chemoattractants or chemorepellents bind MCPs at its extracellular domain; an intracellular signaling domain relays the changes in concentration of these chemotactic ligands to downstream proteins like that of CheA which then relays this signal to flagellar motors via phosphorylated CheY (CheY-P).
CheY-P can then control flagellar rotation influencing the direction of cell motility.
For ''E.coli'', ''
S. meliloti'', and ''
R. spheroids,'' the binding of chemoattractants to MCPs inhibit CheA and therefore CheY-P activity, resulting in smooth runs, but for ''
B. substilis'', CheA activity increases.
Methylation events in ''E.coli'' cause MCPs to have lower affinity to chemoattractants which causes increased activity of CheA and CheY-P resulting in tumbles.
In this way cells are able to adapt to the immediate chemoattractant concentration and detect further changes to modulate cell motility.
Chemoattractants in eukaryotes are well characterized for immune cells.
Formyl peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
...
s, such as
fMLF, attract
leukocytes
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
such as
neutrophil
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
s and
macrophages, causing movement toward infection sites.
Non-acylated methioninyl peptides do not act as chemoattractants to neutrophils and macrophages.
Leukocytes also move toward chemoattractants C5a, a
complement
A complement is something that completes something else.
Complement may refer specifically to:
The arts
* Complement (music), an interval that, when added to another, spans an octave
** Aggregate complementation, the separation of pitch-clas ...
component, and
pathogen
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
-specific ligands on bacteria.
Mechanisms concerning chemorepellents are less known than chemoattractants. Although chemorepellents work to confer an avoidance response in organisms,
''Tetrahymena thermophila'' adapt to a chemorepellent,
Netrin-1 peptide, within 10 minutes of exposure; however, exposure to chemorepellents such as
GTP,
PACAP-38, and
nociceptin show no such adaptations. GTP and
ATP are chemorepellents in micro-molar concentrations to both ''Tetrahymena'' and ''
Paramecium
''
''Paramecium'' ( , ; also spelled ''Paramoecium'') is a genus of eukaryotic, unicellular ciliates, commonly studied as a representative of the ciliate group. ''Paramecia'' are widespread in freshwater, brackish, and marine environments and a ...
''. These organisms avoid these molecules by producing avoiding reactions to re-orient themselves away from the gradient.
Eukaryotic chemotaxis
The mechanism of chemotaxis that
eukaryotic
Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...
cells employ is quite different from that in the bacteria ''E. coli''; however, sensing of chemical gradients is still a crucial step in the process. Due to their small size and other biophysical constraints, ''E. coli'' cannot directly detect a concentration gradient. Instead, they employ temporal gradient sensing, where they move over larger distances several times their own width and measure the rate at which perceived chemical concentration changes.
Eukaryotic cells are much larger than prokaryotes and have receptors embedded uniformly throughout the
cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
.
Eukaryotic chemotaxis involves detecting a concentration gradient spatially by comparing the asymmetric activation of these receptors at the different ends of the cell.
Activation of these receptors results in migration towards chemoattractants, or away from chemorepellants.
In mating yeast, which are non-motile, patches of polarity proteins on the cell cortex can relocate in a chemotactic fashion up pheromone gradients.
It has also been shown that both prokaryotic and eukaryotic cells are capable of chemotactic memory.
In prokaryotes, this mechanism involves the
methylation of receptors called
methyl-accepting chemotaxis proteins (MCPs).
This results in their desensitization and allows prokaryotes to "remember" and adapt to a chemical gradient.
In contrast, chemotactic memory in eukaryotes can be explained by the Local Excitation Global Inhibition (LEGI) model.
LEGI involves the balance between a fast excitation and delayed inhibition which controls downstream signaling such as
Ras activation and
PIP3
Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid th ...
production.
Levels of receptors, intracellular signalling pathways and the effector mechanisms all represent diverse, eukaryotic-type components. In eukaryotic unicellular cells, amoeboid movement and cilium or the eukaryotic flagellum are the main effectors (e.g.,
Amoeba
An amoeba (; less commonly spelled ameba or amœba; plural ''am(o)ebas'' or ''am(o)ebae'' ), often called an amoeboid, is a type of cell or unicellular organism with the ability to alter its shape, primarily by extending and retracting pseudop ...
or
Tetrahymena
''Tetrahymena'', a unicellular eukaryote, is a genus of free-living ciliates. The genus Tetrahymena is the most widely studied member of its phylum. It can produce, store and react with different types of hormones. Tetrahymena cells can recog ...
). Some eukaryotic cells of
higher vertebrate
Amniotes are a clade of tetrapod vertebrates that comprises sauropsids (including all reptiles and birds, and extinct parareptiles and non-avian dinosaurs) and synapsids (including pelycosaurs and therapsids such as mammals). They are distingu ...
origin, such as
immune cells
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
also move to where they need to be. Besides immune competent cells (
granulocyte,
monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
,
lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
) a large group of cells—considered previously to be fixed into tissues—are also motile in special physiological (e.g.,
mast cell
A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a par ...
,
fibroblast,
endothelial cells
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
) or pathological conditions (e.g.,
metastases
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then ...
). Chemotaxis has high significance in the early phases of
embryogenesis as development of
germ layers
A germ layer is a primary layer of cells that forms during embryonic development. The three germ layers in vertebrates are particularly pronounced; however, all eumetazoans (animals that are sister taxa to the sponges) produce two or three pr ...
is guided by gradients of signal molecules.
Motility
Unlike motility in bacterial chemotaxis, the mechanism by which eukaryotic cells physically move is unclear. There appear to be mechanisms by which an external chemotactic gradient is sensed and turned into an intracellular
PIP3
Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid th ...
gradient, which results in a gradient and the activation of a signaling pathway, culminating in the
polymerisation
In polymer chemistry, polymerization (American English), or polymerisation (British English), is a process of reacting monomer molecules together in a chemical reaction to form polymer chains or three-dimensional networks. There are many for ...
of
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...
filaments. The growing distal end of actin filaments develops connections with the internal surface of the plasma membrane via different sets of peptides and results in the formation of anterior
pseudopods
A pseudopod or pseudopodium (plural: pseudopods or pseudopodia) is a temporary arm-like projection of a eukaryotic cell membrane that is emerged in the direction of movement. Filled with cytoplasm, pseudopodia primarily consist of actin filamen ...
and posterior
uropods
Uropods are posterior appendages found on a wide variety of crustaceans. They typically have functions in locomotion.
Definition
Uropods are often defined as the appendages of the last body segment of a crustacean. An alternative definition sugg ...
.
Cilia of eukaryotic cells can also produce chemotaxis; in this case, it is mainly a Ca
2+-dependent induction of the
microtubular system of the
basal body
A basal body (synonymous with basal granule, kinetosome, and in older cytological literature with blepharoplast) is a protein structure found at the base of a eukaryotic undulipodium (cilium or flagellum). The basal body was named by Theodor Wi ...
and the beat of the 9 + 2 microtubules within cilia. The orchestrated beating of hundreds of cilia is synchronized by a submembranous system built between basal bodies.
The details of the signaling pathways are still not totally clear.
Chemotaxis-related migratory responses
Chemotaxis refers to the directional migration of cells in response to chemical gradients; several variations of chemical-induced migration exist as listed below.
* ''
Chemokinesis Chemokinesis is chemically prompted kinesis, a motile response of unicellular prokaryotic or eukaryotic organisms to chemicals that cause the cell to make some kind of change in their migratory/swimming behaviour. Changes involve an increase or de ...
'' refers to an increase in cellular motility in response to chemicals in the surrounding environment. Unlike chemotaxis, the migration stimulated by chemokinesis lacks directionality, and instead increases environmental scanning behaviors.
* In ''
haptotaxis Haptotaxis (from Greek ἅπτω (hapto, "touch, fasten") and τάξις (taxis, "arrangement, order")) is the directional motility or outgrowth of cells, e.g. in the case of axonal outgrowth, usually up a gradient of cellular adhesion sites or sub ...
'' the
gradient
In vector calculus, the gradient of a scalar-valued differentiable function of several variables is the vector field (or vector-valued function) \nabla f whose value at a point p is the "direction and rate of fastest increase". If the gr ...
of the chemoattractant is expressed or bound on a surface, in contrast to the classical model of chemotaxis, in which the gradient develops in a soluble fluid.
The most common biologically active haptotactic surface is the
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide s ...
(ECM); the presence of bound
ligands is responsible for induction of transendothelial migration and
angiogenesis.
* ''
Necrotaxis Necrotaxis embodies a special type of chemotaxis when the chemoattractant molecules are released from necrotic or apoptotic cells. Investigations of necrotaxis proved that ability to sense substances released from dying cells is present in unicell ...
'' embodies a special type of chemotaxis when the chemoattractant molecules are released from
necrotic
Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...
or
apoptotic
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes incl ...
cells. Depending on the chemical character of released substances, necrotaxis can accumulate or repel cells, which underlines the pathophysiological significance of this phenomenon.
Receptors
In general, eukaryotic cells sense the presence of chemotactic stimuli through the use of 7-transmembrane (or serpentine) heterotrimeric
G-protein
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their act ...
-coupled receptors, a class representing a significant portion of the
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding g ...
. Some members of this gene superfamily are used in eyesight (rhodopsins) as well as in olfaction (smelling). The main classes of chemotaxis receptors are triggered by:
* Formyl peptides -
formyl peptide receptors (FPR),
*
Chemokines
Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition ...
-
chemokine receptor
Chemokine receptors are cytokine receptors found on the surface of certain cells that interact with a type of cytokine called a chemokine. There have been 20 distinct chemokine receptors discovered in humans. Each has a rhodopsin-like 7-trans ...
s (CCR or CXCR), and
*
Leukotrienes
Leukotrienes are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxygenase.
Leukotri ...
-
leukotriene receptor
The leukotriene (LT) receptors are G protein-coupled receptors that bind and are activated by the leukotrienes. They include the following proteins:
* Leukotriene B4 receptors (BLTRs) – bind to and are activated by LTB4:
** BLT1 ( Leukotriene B ...
s (BLT).
However, induction of a wide set of membrane receptors (e.g.,
cyclic nucleotide
A cyclic nucleotide (cNMP) is a single-phosphate nucleotide with a cyclic bond arrangement between the sugar and phosphate groups. Like other nucleotides, cyclic nucleotides are composed of three functional groups: a sugar, a nitrogenous base, a ...
s,
amino acids,
insulin, vasoactive peptides) also elicit migration of the cell.
Chemotactic selection
While some chemotaxis receptors are expressed in the surface membrane with long-term characteristics, as they are determined genetically, others have short-term dynamics, as they are assembled ''ad hoc'' in the presence of the ligand. The diverse features of the chemotaxis receptors and ligands allows for the possibility of selecting chemotactic responder cells with a simple chemotaxis assay By
chemotactic selection Chemotaxis receptors are expressed in the surface membrane with diverse dynamics, some of them have long-term characteristics as they are determined genetically, others have short-term moiety as their assembly is induced ''ad hoc'' in the presence o ...
, we can determine whether a still-uncharacterized molecule acts via the long- or the short-term receptor pathway. The term ''chemotactic selection'' is also used to designate a technique that separates eukaryotic or prokaryotic cells according to their chemotactic responsiveness to selector ligands.
Chemotactic ligands
The number of molecules capable of eliciting chemotactic responses is relatively high, and we can distinguish primary and secondary chemotactic molecules. The main groups of the primary ligands are as follows:
* ''Formyl peptides'' are di-, tri-, tetrapeptides of bacterial origin, formylated on the N-terminus of the peptide. They are released from bacteria in vivo or after decomposition of the cell[ a typical member of this group is the N-formylmethionyl-leucyl-phenylalanine (abbreviated fMLF or fMLP). Bacterial fMLF is a key component of inflammation has characteristic chemoattractant effects in neutrophil granulocytes and monocytes. The chemotactic factor ligands and receptors related to formyl peptides are summarized in the related article, Formyl peptide receptors.
* ''Complement 3a (C3 (complement), C3a) and complement 5a (Complement component 5a, C5a)'' are intermediate products of the complement cascade. Their synthesis is joined to the three alternative pathways (classical, lectin-dependent, and alternative) of complement activation by a convertase enzyme. The main target cells of these derivatives are neutrophil granulocytes and monocytes as well.
* ''
Chemokines
Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition ...
'' belong to a special class of
cytokines; not only do their groups (C, CC, CXC, CX
3C chemokines) represent structurally related molecules with a special arrangement of disulfide bridges but also their target cell specificity is diverse. CC chemokines act on monocytes (e.g.,
RANTES
Chemokine (C-C motif) ligand 5 (also CCL5) is a protein which in humans is encoded by the ''CCL5'' gene. The gene has been discovered in 1990 by ''in situ'' hybridisation and it is localised on 17q11.2-q12 chromosome. It is also known as RANTES ...
), and CXC chemokines are neutrophil granulocyte-specific (e.g.,
IL-8). Investigations of the three-dimensional structures of chemokines provided evidence that a characteristic composition of beta-sheets and an alpha helix provides expression of sequences required for interaction with the chemokine receptors. Formation of dimers and their increased biological activity was demonstrated by crystallography of several chemokines, e.g. IL-8.
*Metabolites of
polyunsaturated fatty acid
Polyunsaturated fatty acids (PUFAs) are fatty acids that contain more than one double bond in their backbone. This class includes many important compounds, such as essential fatty acids and those that give drying oils their characteristic proper ...
s
** ''
Leukotrienes
Leukotrienes are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxygenase.
Leukotri ...
'' are
eicosanoid
Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a s ...
lipid mediators made by the metabolism of
arachidonic acid by
ALOX5
Arachidonate 5-lipoxygenase, also known as ALOX5, 5-lipoxygenase, 5-LOX, or 5-LO, is a non-heme iron-containing enzyme (EC 1.13.11.34) that in humans is encoded by the ''ALOX5'' gene. Arachidonate 5-lipoxygenase is a member of the lipoxygenase fa ...
(also termed 5-lipoxygenase). Their most prominent member with chemotactic factor activity is
leukotriene B4
Leukotriene B4 (LTB4) is a leukotriene involved in inflammation. It has been shown to promote insulin resistance in obese mice.
Biochemistry
Leukotriene B4 (LTB4) is a leukotriene involved in inflammation. It is produced from leukocytes in r ...
, which elicits adhesion, chemotaxis, and aggregation of leukocytes. The chemoattractant action of LTB4 is induced via either of two
G protein–coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
s, BLT1 and
BLT2, which are highly expressed in cells involved in
inflammation
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
and
allergy
Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derm ...
.
** The family of
5-Hydroxyicosatetraenoic acid eicosanoids are arachidonic acid metabolites also formed by ALOX5. Three members of the family form naturally and have prominent chemotactic activity. These, listed in order of decreasing potency, are: ''
5-oxo-eicosatetraenoic acid'', ''5-oxo-15-hydroxy-eicosatetraenoic acid'', and ''
5-Hydroxyeicosatetraenoic acid''. This family of agonists stimulates chemotactic responses in human
eosinophils
Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...
,
neutrophils, and
monocytes by binding to the
Oxoeicosanoid receptor 1, which like the receptors for leukotriene B4, is a G protein-coupled receptor.
Aside from the skin,
neutrophils are the body's first line of defense against
bacterial
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were amon ...
infections. After leaving nearby blood vessels, these cells recognize chemicals produced by bacteria in a cut or scratch and migrate "toward the smell".
**''5-hydroxyeicosatrieonic acid'' and ''5-oxoeicosatrienoic acid'' are metabolites of
Mead acid
Mead acid is an omega-9 fatty acid, first characterized by James F. Mead. As with some other omega-9 polyunsaturated fatty acids, animals can make Mead acid ''de novo''. Its elevated presence in the blood is an indication of essential fatty acid ...
(5''Z'',8''Z'',11''Z''-eicosatrirenoid acid); they stimulate leukocyte chemotaxis through the oxoeicosanoid receptor 1
with 5-oxoeicosatrienoic acid being as potent as its arachidonic acid-derived analog, 5-oxo-eicosatetraenoic acid, in stimulating human blood
eosinophil
Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...
and
neutrophil
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
chemotaxis.
**''
12-Hydroxyeicosatetraenoic acid'' is an eicosanoid metabolite of arachidonic acid made by
ALOX12 which stimulates leukocyte chemotaxis through the leukotriene B4 receptor, BLT2.
**''
Prostaglandin D2'' is an eicosanoid metabolite of arachidononic acid made by
cyclooxygenase 1
Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, ) that is responsible for formation of prostanoids, including thromboxane and prostaglandins such as prosta ...
or
cyclooxygenase 2
Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) (The HUGO official symbol is PTGS2; HGNC ID, HGNC:9605), also known as cyclooxygenase-2 or COX-2, is an enzyme that in humans is encoded by the ''PTGS2'' gene ...
that stimulates chemotaxis through the
Prostaglandin DP2 receptor
Prostaglandin D2 receptor 2 (DP2 or CRTH2) is a human protein encoded by the PTGDR2 gene and GPR44. DP2 has also been designated as CD294 (cluster of differentiation 294). It is a member of the class of prostaglandin receptors which bind with an ...
. It elicits chemotactic responses in eosinophils, basophils, and
T helper cell
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are consider ...
s of the Th2 subtype.
**''
12-Hydroxyheptadecatrienoic acid
1 (one, unit, unity) is a number representing a single or the only entity. 1 is also a numerical digit and represents a single unit of counting or measurement. For example, a line segment of ''unit length'' is a line segment of length 1. I ...
'' is a non-eicosanoid metabolite of arachidonic acid made by cyclooxygenase 1 or cyclooxygenase 2 that stimulates leukocyte chemataxis though the leukotriene B4 receptor, BLT2.
**''15-oxo-eicosatetraenoic acid'' is an eicosanoid metabolite of arachidonic acid made my
ALOX15
ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically importa ...
; it has weak chemotactic activity for human monocytes (sees
15-Hydroxyeicosatetraenoic acid#15-oxo-ETE). The receptor or other mechanism by which this metabolite stimulates chemotaxis has not been elucidated.
Chemotactic range fitting
![chtxCRF2](https://upload.wikimedia.org/wikipedia/commons/6/60/ChtxCRF2.png)
Chemotactic responses elicited by
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...
-
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
interactions vary with the concentration of the ligand. Investigations of ligand families (e.g.
amino acids or
oligopeptide
An oligopeptide, often just called peptide ('' oligo-'', "a few"), consists of two to twenty amino acids and can include dipeptides, tripeptides, tetrapeptides, and pentapeptides. Some of the major classes of naturally occurring oligopeptides in ...
s) demonstrates that
chemoattractant activity occurs over a wide range, while
chemorepellent activities have narrow ranges.
Clinical significance
A changed migratory potential of cells has relatively high importance in the development of several clinical symptoms and syndromes.
Altered chemotactic activity of extracellular (e.g.,
Escherichia coli
''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Esc ...
) or intracellular (e.g.,
Listeria monocytogenes
''Listeria monocytogenes'' is the species of pathogenic bacteria that causes the infection listeriosis. It is a facultative anaerobic bacterium, capable of surviving in the presence or absence of oxygen. It can grow and reproduce inside the host ...
) pathogens itself represents a significant clinical target. Modification of endogenous chemotactic ability of these microorganisms by pharmaceutical agents can decrease or inhibit the ratio of infections or spreading of infectious diseases.
Apart from infections, there are some other diseases wherein impaired chemotaxis is the primary etiological factor, as in
Chédiak–Higashi syndrome
Chédiak–Higashi syndrome (CHS) is a rare autosomal recessive disorder that arises from a mutation of a lysosomal trafficking regulator protein, which leads to a decrease in phagocytosis. The decrease in phagocytosis results in recurrent pyogeni ...
, where giant intracellular vesicles inhibit normal migration of cells.
Mathematical models
Several mathematical models of chemotaxis were developed depending on the type of
* Migration (e.g., basic differences of bacterial swimming, movement of unicellular eukaryotes with
cilia/
flagellum
A flagellum (; ) is a hairlike appendage that protrudes from certain plant and animal sperm cells, and from a wide range of microorganisms to provide motility. Many protists with flagella are termed as flagellates.
A microorganism may have f ...
and
amoeboid
An amoeba (; less commonly spelled ameba or amœba; plural ''am(o)ebas'' or ''am(o)ebae'' ), often called an amoeboid, is a type of cell or unicellular organism with the ability to alter its shape, primarily by extending and retracting pseudopo ...
migration)
* Physico-chemical characteristics of the chemicals (e.g.,
diffusion
Diffusion is the net movement of anything (for example, atoms, ions, molecules, energy) generally from a region of higher concentration to a region of lower concentration. Diffusion is driven by a gradient in Gibbs free energy or chemica ...
) working as ligands
* Biological characteristics of the ligands (attractant, neutral, and repellent molecules)
* Assay systems applied to evaluate chemotaxis (see incubation times, development, and stability of concentration gradients)
* Other environmental effects possessing direct or indirect influence on the migration (lighting, temperature, magnetic fields, etc.)
Although interactions of the factors listed above make the behavior of the solutions of mathematical models of chemotaxis rather complex, it is possible to describe the basic phenomenon of chemotaxis-driven motion in a straightforward way. Indeed, let us denote with
the spatially non-uniform concentration of the chemo-attractant and
as its gradient. Then the chemotactic cellular flow (also called current)
that is generated by the chemotaxis is linked to the above gradient by the law:
:
where
is the spatial density of the cells and
is the so-called ’Chemotactic coefficient’ -
is often not constant, but a decreasing function of the chemo-attractant. For some quantity
that is subject to total flux
and generation/destruction term
, it is possible to formulate a
continuity equation:
:
where
is the
divergence
In vector calculus, divergence is a vector operator that operates on a vector field, producing a scalar field giving the quantity of the vector field's source at each point. More technically, the divergence represents the volume density of t ...
. This general equation applies to both the cell density and the chemo-attractant. Therefore, incorporating a diffusion flux into the total flux term, the interactions between these quantities are governed by a set of coupled
reaction-diffusion partial differential equations
In mathematics, a partial differential equation (PDE) is an equation which imposes relations between the various partial derivatives of a multivariable function.
The function is often thought of as an "unknown" to be solved for, similarly to ...
describing the change in
and
:
:
where
describes the growth in cell density,
is the kinetics/source term for the chemo-attractant, and the diffusion coefficients for cell density and the chemo-attractant are respectively
and
.
Spatial ecology
Spatial ecology studies the ultimate distributional or spatial unit occupied by a species. In a particular habitat shared by several species, each of the species is usually confined to its own microhabitat or spatial niche because two species in ...
of soil microorganisms is a function of their chemotactic sensitivities towards substrate and fellow organisms.
The chemotactic behavior of the bacteria was proven to lead to non-trivial population patterns even in the absence of environmental heterogeneities. The presence of structural pore scale heterogeneities has an extra impact on the emerging bacterial patterns.
Measurement of chemotaxis
A wide range of techniques is available to evaluate chemotactic activity of cells or the chemoattractant and chemorepellent character of ligands.
The basic requirements of the measurement are as follows:
* Concentration gradients can develop relatively quickly and persist for a long time in the system
* Chemotactic and chemokinetic activities are distinguished
* Migration of cells is free toward and away on the axis of the concentration gradient
* Detected responses are the results of active migration of cells
Despite the fact that an ideal
chemotaxis assay
Chemotaxis assays are experimental tools for evaluation of chemotactic ability of prokaryotic or eukaryotic cells.
A wide variety of techniques have been developed. Some techniques are qualitative - allowing an investigator to approximately dete ...
is still not available, there are several protocols and pieces of equipment that offer good correspondence with the conditions described above. The most commonly used are summarised in the table below:
Artificial chemotactic systems
''Chemical robots'' that use artificial chemotaxis to navigate autonomously have been designed. Applications include targeted delivery of drugs in the body. More recently, enzyme molecules have also shown positive chemotactic behavior in the gradient of their substrates. The thermodynamically-favorable binding of enzymes to their specific substrates is recognized as the origin of enzymatic chemotaxis. Additionally, enzymes in cascades have also shown substrate-driven chemotactic aggregation.
Apart from active enzymes, non-reacting molecules also show chemotactic behavior. This has been demonstrated by using dye molecules that move directionally in gradients of polymer solution through favorable hydrophobic interactions.
See also
*
McCutcheon index
*
Tropism
A tropism is a biological phenomenon, indicating growth or turning movement of a biological organism, usually a plant, in response to an environmental stimulus. In tropisms, this response is dependent on the direction of the stimulus (as oppos ...
*
Durotaxis
Durotaxis is a form of cell migration in which cells are guided by rigidity gradients, which arise from differential structural properties of the extracellular matrix (ECM). Most normal cells migrate up rigidity gradients (in the direction of great ...
*
Haptotaxis Haptotaxis (from Greek ἅπτω (hapto, "touch, fasten") and τάξις (taxis, "arrangement, order")) is the directional motility or outgrowth of cells, e.g. in the case of axonal outgrowth, usually up a gradient of cellular adhesion sites or sub ...
*
Mechanotaxis
*
Plithotaxis
*
Thin layers (oceanography)
Thin layers are concentrated aggregations of phytoplankton and zooplankton in coastal and offshore waters that are vertically compressed to thicknesses ranging from several centimeters up to a few meters and are horizontally extensive, sometim ...
References
Further reading
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External links
ChemotaxisNeutrophil ChemotaxisCell Migration GatewayDownloadable Matlab chemotaxis simulatorBacterial Chemotaxis Interactive Simulator (web-app)
{{Taxes (Biology)
Motile cells
Perception
Taxes (biology)
Transmembrane receptors
Transport phenomena