The mechanism of chemotaxis that
eukaryotic 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. In prokaryotes, this mechanism involves the
methylation of receptors called
methyl-accepting chemotaxis proteins (MCPs). LEGI involves the balance between a fast excitation and delayed inhibition which controls downstream signaling such as
Ras activation and
PIP3 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 or
Tetrahymena). Some eukaryotic cells of
higher vertebrate origin, such as
immune cells also move to where they need to be. Besides immune competent cells (
granulocyte,
monocyte,
lymphocyte) a large group of cells—considered previously to be fixed into tissues—are also motile in special physiological (e.g.,
mast cell,
fibroblast,
endothelial cells) or pathological conditions (e.g.,
metastases). Chemotaxis has high significance in the early phases of
embryogenesis as development of
germ layers is guided by gradients of signal molecules.
Detection of a gradient of chemoattractant The specific molecule/s that allow a eukaryotic cells detect a gradient of chemoattractant ligands (that is, a sort of the molecular compass that detects the direction of a chemoattractant) seems to change depending on the cell and chemoattractant receptor involved or even the concentration of the chemoattractant. However, these molecules apparently are activated independently of the motility of the cell. That is, even an immnobilized cell is still able to detect the direction of a chemoattractant. There appear to be mechanisms by which an external chemotactic gradient is sensed and turned into an intracellular Ras and
PIP3 gradients, which results in a gradient and the activation of a signaling pathway, culminating in the
polymerisation of
actin 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 and posterior
uropods.
Cilia of eukaryotic cells can also produce chemotaxis; in this case, it is mainly a Ca2+-dependent induction of the
microtubular system of the
basal body 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 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 the
gradient 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 (ECM); the presence of bound
ligands is responsible for induction of transendothelial migration and
angiogenesis. •
Necrotaxis embodies a special type of chemotaxis when the chemoattractant molecules are released from
necrotic or
apoptotic 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-coupled receptors, a class representing a significant portion of the
genome. 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 -
chemokine receptors (CCR or CXCR), and •
Leukotrienes -
leukotriene receptors (BLT). However, induction of a wide set of membrane receptors (e.g.,
cyclic nucleotides,
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, 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 and 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 (C3a) and complement 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 belong to a special class of
cytokines; not only do their groups (C, CC, CXC, CX3C 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), 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 acids •
Leukotrienes are
eicosanoid lipid mediators made by the metabolism of
arachidonic acid by
ALOX5 (also termed 5-lipoxygenase). Their most prominent member with chemotactic factor activity is
leukotriene B4, which elicits adhesion, chemotaxis, and aggregation of leukocytes. The chemoattractant action of LTB4 is induced via either of two
G protein–coupled receptors, BLT1 and
BLT2, which are highly expressed in cells involved in
inflammation and
allergy. • 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,
neutrophils, and
monocytes by binding to the
Oxoeicosanoid receptor 1, which like the receptors for leukotriene B4, is a G protein-coupled receptor. with 5-oxoeicosatrienoic acid being as potent as its arachidonic acid-derived analog, 5-oxo-eicosatetraenoic acid, in stimulating human blood
eosinophil and
neutrophil chemotaxis. •
12-Hydroxyheptadecatrienoic acid is a non-eicosanoid metabolite of arachidonic acid made by cyclooxygenase 1 or cyclooxygenase 2 that stimulates leukocyte chemotaxis though the leukotriene B4 receptor, BLT2. •
15-oxo-eicosatetraenoic acid is an eicosanoid metabolite of arachidonic acid made my
ALOX15; 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 Chemotactic responses elicited by
ligand-
receptor interactions vary with the concentration of the ligand. Investigations of ligand families (e.g.
amino acids or
oligopeptides) demonstrates that
chemoattractant activity occurs over a wide range, while
chemorepellent activities have narrow ranges. ==Clinical significance==