Lipid signaling
Encyclopedia
Lipid signaling, broadly defined, refers to any biological signaling
event involving a lipid
messenger that binds a protein target, such as a receptor
, kinase
or phosphatase
, which in turn mediate the effects of these lipids on specific cellular responses. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms (such as monoamine neurotransmission
) because lipids can freely diffuse through membranes
(see osmosis
.) One consequence of this is that lipid messengers cannot be stored in vesicles
prior to release and so are often biosynthesized
"on demand" at their intended site of action. As such, many lipid signaling molecules cannot circulate freely in solution but, rather, exist bound to special carrier proteins in serum
.
(Cer) can be generated by the breakdown of sphingomyelin
(SM) by sphingomyelinases (SMases), which are enzymes that hydrolyze the phosphocholine
group from the sphingosine
backbone. Alternatively, this sphingosine
-derived lipid
(sphingolipid
) can be synthesized from scratch (de novo) by the enzymes serine palmitoyl transferase (SPT) and ceramide
synthase
in organelles such as the endoplasmic reticulum
(ER) and possibly, in the mitochondria-associated membranes (MAMs) and the perinuclear membranes. Being located in the metabolic hub, ceramide leads to the formation of other sphingolipids, with the C1 hydroxyl
(-OH) group as the major site of modification. A sugar can be attached to ceramide
(glycosylation) through the action of the enzymes, glucosyl or galactosyl ceramide
synthases. Ceramide can also be broken down by enzymes called ceramidases, leading to the formation of sphingosine
, Moreover, a phosphate group can be attached to ceramide (phosphorylation) by the enzyme, ceramide
kinase
. It is also possible to regenerate sphingomyelin from ceramide by accepting a phosphocholine
headgroup from phosphatidylcholine
(PC) by the action of an enzyme called sphingomyelin
synthase
. The latter process results in the formation of diacylglycerol (DAG) from PC.
Ceramide
contains two hydrophobic ("water-fearing") chains and a neutral headgroup. Consequently, it has limited solubility in water and is restricted within the organelle
where it was formed. Also, because of its hydrophobic nature, ceramide readily flip-flops across membranes as supported by studies in membrane models and membranes from red blood cells (erythrocytes). However, ceramide
can possibly interact with other lipids to form bigger regions called microdomains which restrict its flip-flopping abilities. This could have immense effects on the signaling functions of ceramide because it is known that ceramide
generated by acidic SMase enzymes in the outer leaflet of an organelle membrane may have different roles compared to ceramide
that is formed in the inner leaflet by the action of neutral SMase enzymes.
Ceramide
mediates many cell-stress responses, including the regulation of programmed cell death (apoptosis
) and cell aging (senescence
). Numerous research works have focused interest on defining the direct protein
targets of action of ceramide. These include enzymes called ceramide
-activated Ser-Thr phosphatases (CAPPs), such as protein
phosphatase
1 and 2A (PP1 and PP2A), which were found to interact with ceramide in studies done in a controlled environment outside of a living organism (in vitro). On the other hand, studies in cells have shown that ceramide-inducing agents such as tumor necrosis factor-alpha α (TNFα) and palmitate induce the ceramide-dependent removal of a phosphate group (dephosphorylation) of the retinoblastoma
gene
product RB and the enzymes, protein kinases B (AKT
protein family) and C α (PKB and PKCα). Moreover, there is also sufficient evidence which implicates ceramide
to the activation of the kinase
suppressor
of Ras
(KSR), PKCζ, and cathepsin D. Interestingly, cathepsin
D has been proposed as the main target for ceramide
formed in organelles called lysosomes, making lysosomal acidic SMase enzymes one of the key players in the mitochondrial pathway of apoptosis
. Ceramide was also shown to activate PKCζ, implicating it to the inhibition
of AKT
, regulation of the voltage difference between the interior and exterior of the cell (membrane potential) and signaling functions that favor apoptosis. Chemotherapeutic agents such as daunorubicin
and etoposide
enhance the de novo synthesis of ceramide
in studies done on mammalian cells. The same results were found for certain inducers of apoptosis
particularly stimulators of receptors in a class of lymphocytes (a type of white blood cell) called B-cells. Regulation of the de novo synthesis of ceramide by palmitate may have a key role in diabetes and the metabolic syndrome
. Experimental evidence shows that there is substantial increase of ceramide
levels upon adding palmitate. Ceramide
accumulation activates PP2A and the subsequent dephosphorylation and inactivation of AKT
, a crucial mediator in metabolic control and insulin
signaling. This results in a substantial decrease in insulin
responsiveness (i.e. to glucose) and in the death of insulin-producing cells in the pancreas called islets of Langerhans
. Inhibition of ceramide synthesis in mice via drug treatments or gene-knockout techniques prevented insulin resistance induced by fatty acids, glucocorticoids or obesity
.
An increase in in vitro activity of acid SMase has been observed after applying multiple stress stimuli such as ultraviolet
(UV) and ionizing radiation, binding of death receptors and chemotherapeutic agents such as platinum
, histone deacetylase inhibitor
s and paclitaxel
. In some studies, SMase activation results to its transport to the plasma membrane and the simultaneous formation of ceramide.
Ceramide transfer protein (CERT) transports ceramide from ER to the Golgi
for the synthesis of SM. CERT is known to bind phosphatidylinositol
phosphates, hinting its potential regulation via phosphorylation
, a step of the ceramide metabolism that can be enzymatically regulated by protein kinases and phosphatases, and by inositol
lipid
metabolic pathways. Up to date, there are at least 26 distinct enzymes with varied subcellular localizations, that act on ceramide as either a substrate or product. Regulation of ceramide levels can therefore be performed by one of these enzymes in distinct organelles by particular mechanisms at various times.
(Sph) is formed by the action of ceramidase
(CDase) enzymes on ceramide in the lysosome
. Sph can also be formed in the extracellular (outer leaflet) side of the plasma membrane by the action of neutral CDase enzyme. Sph then is either recycled back to ceramide or phosphorylated by one of the sphingosine kinase
enzymes, SK1 and SK2. The product sphingosine-1-phosphate
(S1P) can be dephosphorylated in the ER to regenerate sphingosine
by certain S1P phosphatase
enzymes within cells, where the salvaged Sph is recycled to ceramide
. Sphingosine
is a single-chain lipid
(usually 18 carbons in length), rendering it to have sufficient solubility in water. This explains its ability to move between membranes and to flip-flop across a membrane. Estimates conducted at physiological pH show that approximately 70% of sphingosine remains in membranes while the remaining 30% is water-soluble. Sph that is formed has sufficient solubility in the liquid found inside cells (cytosol
). Thus, Sph may come out of the lysosome
and move to the ER without the need for transport via proteins or membrane-enclosed sacs called vesicles
. However, its positive charge favors partitioning in lysosomes. It is proposed that the role of SK1 located near or in the lysosome is to ‘trap’ Sph via phosphorylation
.
It is important to note that since sphingosine exerts surfactant
activity, it is one of the sphingolipids found at lowest cellular levels. The low levels of Sph and their increase in response to stimulation of cells, primarily by activation of ceramidase
by growth-inducing proteins such as platelet-derived growth factor
and insulin-like growth factor
, is consistent with its function as a second messenger. It was found that immediate hydrolysis
of only 3 to 10% of newly-generated ceramide
may double the levels of Sph. Treatment of HL60 cells (a type of leukemia cell line) by a plant-derived organic compound called phorbol
ester increased Sph levels threefold, whereby the cells differentiated into white blood cells called macrophages. Treatment of the same cells by exogenous Sph caused apoptosis
. A specific protein kinase
phosphorylates 14-3-3, otherwise known as sphingosine-dependent protein kinase 1 (SDK1), only in the presence of Sph.
Sph is also known to interact with protein targets such as the protein kinase
H homologue (PKH) and the yeast protein kinase (YPK). These targets in turn mediate the effects of Sph and its related sphingoid bases, with known roles in regulating the actin
cytoskeleton
, endocytosis
, the cell cycle
and apoptosis
. It is important to note however that the second messenger function of Sph is not yet established unambiguously.
(S1P), like Sph, is composed of a single hydrophobic chain and has sufficient solubility to move between membranes. S1P is formed by phosphorylation
of sphingosine
by sphingosine kinase
(SK). The phosphate group of the product can be detached (dephosphorylated) to regenerate sphingosine via S1P phosphatase
enzymes or S1P can be broken down by S1P lyase
enzymes to ethanolamine phosphate and hexadecenal. Similar to Sph, its second messenger function is not yet clear. However, there is substantial evidence that implicates S1P to cell survival, cell migration
, and inflammation
. Certain growth-inducing proteins such as platelet-derived growth factor
(PDGF), insulin-like growth factor
(IGF) and vascular endothelial growth factor
(VEGF) promote the formation of SK enzymes, leading to increased levels of S1P. Other factors that induce SK include cellular communication molecules called cytokines, such as tumor necrosis factor α (TNFα) and interleukin-1 (IL-1), hypoxia
or lack of oxygen supply in cells, oxidized low-density lipoproteins (oxLDL) and several immune complexes.
S1P is probably formed at the inner leaflet of the plasma membrane in response to TNFα and other receptor activity-altering compounds called agonists. S1P, being present in low nanomolar concentrations in the cell, has to interact with high-affinity receptors that are capable of sensing their low levels. So far, the only identified receptors for S1P are the high-affinity G protein-coupled receptors (GPCRs), also known as S1P receptors (S1PRs). S1P is required to reach the extracellular side (outer leaflet) of the plasma membrane to interact with S1PRs and launch typical GPCR signaling pathways. However, the zwitterionic headgroup of S1P makes it unlikely to flip-flop spontaneously. To overcome this difficulty, the ATP-binding cassette (ABC) transporter C1 (ABCC1) serves as the "exit door" for S1P. On the other hand, the cystic fibrosis transmembrane regulator (CFTR) serves as the means of entry for S1P into the cell. In contrast to its low intracellular concentration, S1P is found in high nanomolar concentrations in serum
where it is bound to albumin
and lipoproteins. Inside the cell, S1P can induce calcium
release independent of the S1PRs—the mechanism of which remains unknown. To date, the intracellular molecular targets for S1P are still unidentified.
The SK1-S1P pathway has been extensively studied in relation to cytokine action, with multiple functions connected to effects of TNFα and IL-1 favoring inflammation
. Studies show that knockdown of key enzymes such as S1P lyase
and S1P phosphatase increased prostaglandin
production, parallel to increase of S1P levels. This strongly suggests that S1P is the mediator of SK1 action and not subsequent compounds. Research done on endothelial and smooth muscle
cells is consistent to the hypothesis that S1P has a crucial role in regulating endothelial cell growth, and movement. Recent work on a sphingosine
analogue, FTY270, demonstrates its ability to act as a potent compound that alters the activity of S1P receptors (agonist
). FTY270 was further verified in clinical tests to have roles in immune modulation, such as that on multiple sclerosis
. This highlights the importance of S1P in the regulation of lymphocyte
function and immunity
. Most of the studies on S1P are used to further understand diseases such as cancer
, arthritis
and inflammation
, diabetes, immune function and neurodegenerative disorders.
in cells serving as precursors
for the formation of over 200 known glycosphingolipids. GluCer is formed by the glycosylation of ceramide in an organelle called Golgi
via enzymes called glucosylceramide synthase (GCS) or by the breakdown of complex glycosphingolipids
(GSLs) through the action of specific hydrolase
enzymes. In turn, certain β-glucosidases hydrolyse these lipids to regenerate ceramide. GluCer appears to be synthesized in the inner leaflet of the Golgi
. Studies show that GluCer has to flip to the inside of the Golgi or transfer to the site of GSL synthesis to initiate the synthesis of complex GSLs. Transferring to the GSL synthesis site is done with the help of a transport protein known as four phosphate adaptor protein 2 (FAPP2) while the flipping to the inside of the Golgi is made possible by the ABC transporter P-glycoprotein
, also known as the multi-drug resistance 1 transporter (MDR1). GluCer is implicated in post-Golgi trafficking and drug resistance particularly to chemotherapeutic agents. For instance, a study demonstrated a correlation between cellular drug resistance
and modifications in GluCer metabolism
.
In addition to their role as building blocks of biological membranes, glycosphingolipids
have long attracted attention because of their supposed involvement in cell growth, differentiation
, and formation of tumors. The production of GluCer from Cer was found to be important in the growth of neurons or brain cells. On the other hand, pharmacological inhibition
of GluCer synthase is being considered a technique to avoid insulin resistance
.
(CK) enzymes on Cer. C1P carry ionic charge at neutral pH and contain two hydrophobic chains making it relatively insoluble in aqueous environment. Thus, C1P reside in the organelle where it was formed and is unlikely to spontaneously flip-flop across membrane bilayers.
C1P activate phospholipase A2
and is found, along with CK, to be a mediator of arachidonic acid
released in cells in response to a protein called interleukin
-1β (IL-1β) and a lipid-soluble molecule that transports calcium ions (Ca2+) across the bilayer, also known as calcium ionophore
. C1P was also previously reported to encourage cell division
(mitogenic) in fibroblasts, block apoptosis
by inhibiting acid SMase in white blood cells within tissues (macrophages) and increase intracellular free calcium
concentrations in thyroid
cells. C1P also has known roles in vesicular
trafficking, cell survival, phagocytosis ("cell eating") and macrophage
degranulation
.
mechanism can be broken down into four steps. First, the agonist activates a membrane-bound receptor. Second, the activated G-protein produces a primary effector. Third, the primary effect stimulates the second messenger synthesis. Fourth, the second messenger activates a certain cellular process.
The G-protein coupled receptors for the PIP2 messenger system produces two effectors, phospholipase C
(PLC) and phosphoinositide 3-kinase
(PI3K). PLC as an effector produces two different second messengers, inositol triphosphate
(IP3) and Diacylglycerol (DAG).
IP3 is soluble and diffuses freely into the cytoplasm. As a second messenger, it is recognised by the inositol triphosphate receptor (IP3R), a Ca2+ channel in the endoplasmic reticulum
(ER) membrane, which stores intracellular Ca2+. The binding of IP3 to IP3R releases Ca2+ from the ER into the normally Ca2+-poor cytoplasm, which then triggers various events of Ca2+ signaling. Specifically in blood vessels, the increase in Ca2+ concentration from IP3 releases nitric oxide, which then diffuses into the smooth muscle tissue and causes constrictions.
DAG remains bound to the membrane by its fatty acid
"tails" where it recruits and activates both conventional and novel members of the protein kinase C
family. Thus, both IP3 and DAG contribute to activation of PKCs.
Phosphoinositide 3-kinase
(PI3K) as an effector phosphorylates phosphatidylinositol bisphosphate
(PIP2) to produce phosphatidylinositol (3,4,5)-trisphosphate
(PIP3). PIP3 has been shown to activate protein kinase B, increase binding to extracellular proteins and ultimately enhance cell survival.
is the result of phospholipase A2
action on phosphatidic acid. The SN-1 position can contain either an ester
bond or an ether
bond, with ether
LPA being found at elevated levels in certain cancers. LPA binds the high-affinity G-protein coupled receptors LPA1
, LPA2
, and LPA3
(also known as EDG2
, EDG4
, and EDG7
, respectively).
is present at high concentrations in plasma and secreted locally at elevated concentrations at sites of inflammation. It is formed by the regulated phosphorylation
of sphingosine
. It acts through five dedicated high-affinity G-protein coupled receptors, S1P1
- S1P5
. Interestingly, targeted deletion of S1P1 results in lethality in mice and deletion of S1P2 results in seizures and deafness. Additionally, a mere 3- to 5-fold elevation in serum S1P concentrations induces sudden cardiac death by an S1P3
-receptor specific mechanism.
phosphatidylcholine
except that it contains an acetyl
-group in the SN-2 position and the SN-1 position contains an ether
-linkage. PAF signals through a dedicated G-protein coupled receptor, PAFR and is inactivated by PAF acetylhydrolase.
, or endocannabinoids, are endogenous lipids that activate cannabinoid receptors. The first such lipid to be isolated was anandamide
which is the arachidonoyl amide
of ethanolamine
. Anandamide is formed via enzymatic release from N-arachidonoyl phosphatidylethanolamine
by enzymes which have not yet been delineated. It activates both the CB1 receptor, found primarily in the central nervous system
, and the CB2 receptor which is found primarily in lymphocytes and the periphery. It is found at very low levels (nM) in most tissues and is inactivated by the fatty acid amide hydrolase. Subsequently, another endocannabinoid was isolated, 2-arachidonoylglycerol
, which is produced when phospholipase C
releases diacylglycerol
which is then converted to 2-AG by diacylglycerol lipase
. 2-AG can also activate both cannabinoid receptors and is inactivated by monoacylglycerol lipase
. It is present at approximately 100-times the concentration of anandamide
in most tissues.
Elevations in either of these lipids causes analgesia and anti-inflammation
but the precise roles played by these two endocannabinoids are still vague and intensive research into their function, metabolism, and regulation is ongoing.
s are formed through oxidation of arachidonic acid
by cyclooxygenase
s and other prostaglandin synthases. There are currently nine known G-protein coupled receptors (eicosanoid receptor
s) that largely mediate prostaglandin physiology (although some prostaglandins activate nuclear receptor
s, see below).
(vitamin A
) derivative responsible for vision. It binds rhodopsin
, a well-characterized GPCR that binds all-cis retinal
in its inactive state. Upon photoisomerization by a photon
the cis-retinal is converted to trans-retinal causing activation of rhodopsin
which ultimately leads to depolarization
of the neuron
thereby enabling visual perception
.
. Mammalian steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestagens.
(vitamin A
) can be metabolized to retinoic acid
which activates nuclear receptors such as the RAR
to control differentiation and proliferation of many types of cells during development.
signaling occurs via GPCRs (see above) although certain prostaglandin
s activate nuclear receptors in the PPAR family. (See article eicosanoid receptor
s for more information).
Cell signaling
Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue...
event involving a lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
messenger that binds a protein target, such as a receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
, kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
or phosphatase
Phosphatase
A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
, which in turn mediate the effects of these lipids on specific cellular responses. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms (such as monoamine neurotransmission
Neurotransmission
Neurotransmission , also called synaptic transmission, is the process by which signaling molecules called neurotransmitters are released by a neuron , and bind to and activate the receptors of another neuron...
) because lipids can freely diffuse through membranes
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
(see osmosis
Osmosis
Osmosis is the movement of solvent molecules through a selectively permeable membrane into a region of higher solute concentration, aiming to equalize the solute concentrations on the two sides...
.) One consequence of this is that lipid messengers cannot be stored in vesicles
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
prior to release and so are often biosynthesized
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
"on demand" at their intended site of action. As such, many lipid signaling molecules cannot circulate freely in solution but, rather, exist bound to special carrier proteins in serum
Serous fluid
In physiology, the term serous fluid is used for various bodily fluids that are typically pale yellow and transparent, and of a benign nature, that fill the inside of body cavities. Serous fluid originates from serous glands, with secretions enriched with proteins and water. Serous fluid may also...
.
Sphingolipid second messengers
Ceramide
CeramideCeramide
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
(Cer) can be generated by the breakdown of sphingomyelin
Sphingomyelin
Sphingomyelin is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds some nerve cell axons. It usually consists of phosphorylcholine and ceramide...
(SM) by sphingomyelinases (SMases), which are enzymes that hydrolyze the phosphocholine
Phosphocholine
Phosphocholine is an intermediate in the synthesis of phosphatidylcholine in tissues. Phosphocholine is made in a reaction, catalyzed by choline kinase, that converts ATP + Choline into Phosphocholine and ADP...
group from the sphingosine
Sphingosine
Sphingosine is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, which forms a primary part of sphingolipids, a class of cell membrane lipids that include sphingomyelin, an important phospholipid.-Functions:...
backbone. Alternatively, this sphingosine
Sphingosine
Sphingosine is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, which forms a primary part of sphingolipids, a class of cell membrane lipids that include sphingomyelin, an important phospholipid.-Functions:...
-derived lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
(sphingolipid
Sphingolipid
Sphingolipids are a class of lipids containing a backbone of sphingoid bases, a set of aliphatic amino alcohols that includes sphingosine. They were discovered in brain extracts in the 1870s and were named for the mythological Sphinx because of their enigmatic nature. These compounds play...
) can be synthesized from scratch (de novo) by the enzymes serine palmitoyl transferase (SPT) and ceramide
Ceramide
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
synthase
Synthase
In biochemistry, a synthase is an enzyme that catalyses a synthesis process.Following the EC number classification, they belong to the group of ligases, with lyases catalysing the reverse reaction....
in organelles such as the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
(ER) and possibly, in the mitochondria-associated membranes (MAMs) and the perinuclear membranes. Being located in the metabolic hub, ceramide leads to the formation of other sphingolipids, with the C1 hydroxyl
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
(-OH) group as the major site of modification. A sugar can be attached to ceramide
Ceramide
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
(glycosylation) through the action of the enzymes, glucosyl or galactosyl ceramide
Ceramide
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
synthases. Ceramide can also be broken down by enzymes called ceramidases, leading to the formation of sphingosine
Sphingosine
Sphingosine is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, which forms a primary part of sphingolipids, a class of cell membrane lipids that include sphingomyelin, an important phospholipid.-Functions:...
, Moreover, a phosphate group can be attached to ceramide (phosphorylation) by the enzyme, ceramide
Ceramide
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
. It is also possible to regenerate sphingomyelin from ceramide by accepting a phosphocholine
Phosphocholine
Phosphocholine is an intermediate in the synthesis of phosphatidylcholine in tissues. Phosphocholine is made in a reaction, catalyzed by choline kinase, that converts ATP + Choline into Phosphocholine and ADP...
headgroup from phosphatidylcholine
Phosphatidylcholine
Phosphatidylcholines are a class of phospholipids that incorporate choline as a headgroup.They are a major component of biological membranes and can be easily obtained from a variety of readily available sources such as egg yolk or soy beans from which they are mechanically extracted or chemically...
(PC) by the action of an enzyme called sphingomyelin
Sphingomyelin
Sphingomyelin is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds some nerve cell axons. It usually consists of phosphorylcholine and ceramide...
synthase
Synthase
In biochemistry, a synthase is an enzyme that catalyses a synthesis process.Following the EC number classification, they belong to the group of ligases, with lyases catalysing the reverse reaction....
. The latter process results in the formation of diacylglycerol (DAG) from PC.
Ceramide
Ceramide
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
contains two hydrophobic ("water-fearing") chains and a neutral headgroup. Consequently, it has limited solubility in water and is restricted within the organelle
Organelle
In cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....
where it was formed. Also, because of its hydrophobic nature, ceramide readily flip-flops across membranes as supported by studies in membrane models and membranes from red blood cells (erythrocytes). However, ceramide
Ceramide
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
can possibly interact with other lipids to form bigger regions called microdomains which restrict its flip-flopping abilities. This could have immense effects on the signaling functions of ceramide because it is known that ceramide
Ceramide
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
generated by acidic SMase enzymes in the outer leaflet of an organelle membrane may have different roles compared to ceramide
Ceramide
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
that is formed in the inner leaflet by the action of neutral SMase enzymes.
Ceramide
Ceramide
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
mediates many cell-stress responses, including the regulation of programmed cell death (apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
) and cell aging (senescence
Senescence
Senescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism...
). Numerous research works have focused interest on defining the direct protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
targets of action of ceramide. These include enzymes called ceramide
Ceramide
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
-activated Ser-Thr phosphatases (CAPPs), such as protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
phosphatase
Phosphatase
A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
1 and 2A (PP1 and PP2A), which were found to interact with ceramide in studies done in a controlled environment outside of a living organism (in vitro). On the other hand, studies in cells have shown that ceramide-inducing agents such as tumor necrosis factor-alpha α (TNFα) and palmitate induce the ceramide-dependent removal of a phosphate group (dephosphorylation) of the retinoblastoma
Retinoblastoma
Retinoblastoma is a rapidly developing cancer that develops in the cells of retina, the light-detecting tissue of the eye. In the developed world, Rb has one of the best cure rates of all childhood cancers , with more than nine out of every ten sufferers surviving into...
gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
product RB and the enzymes, protein kinases B (AKT
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
protein family) and C α (PKB and PKCα). Moreover, there is also sufficient evidence which implicates ceramide
Ceramide
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
to the activation of the kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
suppressor
Suppressor
A suppressor, sound suppressor, sound moderator, or silencer, is a device attached to or part of the barrel of a firearm which reduces the amount of noise and flash generated by firing the weapon....
of Ras
Ras
Ras is the name given to a family of related proteins found inside cells, including human cells. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells...
(KSR), PKCζ, and cathepsin D. Interestingly, cathepsin
Cathepsin
Cathepsins are proteases: proteins that break apart other proteins, found in many types of cells including those in all animals. There are approximately a dozen members of this family, which are distinguished by their structure, catalytic mechanism, and which proteins they cleave...
D has been proposed as the main target for ceramide
Ceramide
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
formed in organelles called lysosomes, making lysosomal acidic SMase enzymes one of the key players in the mitochondrial pathway of apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. Ceramide was also shown to activate PKCζ, implicating it to the inhibition
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
of AKT
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
, regulation of the voltage difference between the interior and exterior of the cell (membrane potential) and signaling functions that favor apoptosis. Chemotherapeutic agents such as daunorubicin
Daunorubicin
Daunorubicin or daunomycin is chemotherapeutic of the anthracycline family that is given as a treatment for some types of cancer. It is most commonly used to treat specific types of leukaemia...
and etoposide
Etoposide
Etoposide phosphate is an anti-cancer agent. It is known in the laboratory as a topoisomerase poison. Etoposide is often incorrectly referred to as a topoisomerase inhibitor in order to avoid using the term "poison" in a clinical setting...
enhance the de novo synthesis of ceramide
Ceramide
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
in studies done on mammalian cells. The same results were found for certain inducers of apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
particularly stimulators of receptors in a class of lymphocytes (a type of white blood cell) called B-cells. Regulation of the de novo synthesis of ceramide by palmitate may have a key role in diabetes and the metabolic syndrome
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...
. Experimental evidence shows that there is substantial increase of ceramide
Ceramide
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
levels upon adding palmitate. Ceramide
Ceramide
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
accumulation activates PP2A and the subsequent dephosphorylation and inactivation of AKT
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
, a crucial mediator in metabolic control and insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
signaling. This results in a substantial decrease in insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
responsiveness (i.e. to glucose) and in the death of insulin-producing cells in the pancreas called islets of Langerhans
Islets of Langerhans
The islets of Langerhans are the regions of the pancreas that contain its endocrine cells. Discovered in 1869 by German pathological anatomist Paul Langerhans at the age of 22, the islets of Langerhans constitute approximately 1 to 2% of the mass of the pancreas...
. Inhibition of ceramide synthesis in mice via drug treatments or gene-knockout techniques prevented insulin resistance induced by fatty acids, glucocorticoids or obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
.
An increase in in vitro activity of acid SMase has been observed after applying multiple stress stimuli such as ultraviolet
Ultraviolet
Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...
(UV) and ionizing radiation, binding of death receptors and chemotherapeutic agents such as platinum
Platinum
Platinum is a chemical element with the chemical symbol Pt and an atomic number of 78. Its name is derived from the Spanish term platina del Pinto, which is literally translated into "little silver of the Pinto River." It is a dense, malleable, ductile, precious, gray-white transition metal...
, histone deacetylase inhibitor
Histone deacetylase inhibitor
Histone deacetylase inhibitors are a class of compounds that interfere with the function of histone deacetylase.HDIs have a long history of use in psychiatry and neurology as mood stabilzers and anti-epileptics...
s and paclitaxel
Paclitaxel
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol...
. In some studies, SMase activation results to its transport to the plasma membrane and the simultaneous formation of ceramide.
Ceramide transfer protein (CERT) transports ceramide from ER to the Golgi
Golgi
Golgi may refer to:*Camillo Golgi , Italian physician and scientist after which the following terms are named:**Golgi apparatus , an organelle in the eukaryotic cell...
for the synthesis of SM. CERT is known to bind phosphatidylinositol
Phosphatidylinositol
Phosphatidylinositol is a negatively charged phospholipid and a minor component in the cytosolic side of eukaryotic cell membranes....
phosphates, hinting its potential regulation via phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
, a step of the ceramide metabolism that can be enzymatically regulated by protein kinases and phosphatases, and by inositol
Inositol
Inositol or cyclohexane-1,2,3,4,5,6-hexol is a chemical compound with formula 6126 or 6, a sixfold alcohol of cyclohexane. It exists in nine possible stereoisomers, of which the most prominent form, widely occurring in nature, is cis-1,2,3,5-trans-4,6-cyclohexanehexol, or myo-inositol...
lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
metabolic pathways. Up to date, there are at least 26 distinct enzymes with varied subcellular localizations, that act on ceramide as either a substrate or product. Regulation of ceramide levels can therefore be performed by one of these enzymes in distinct organelles by particular mechanisms at various times.
Sphingosine
SphingosineSphingosine
Sphingosine is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, which forms a primary part of sphingolipids, a class of cell membrane lipids that include sphingomyelin, an important phospholipid.-Functions:...
(Sph) is formed by the action of ceramidase
Ceramidase
Ceramidase is an enzyme which cleaves fatty acids from ceramide, producing sphingosine which in turn is phosphorylated by a sphingosine kinase to form sphingosine-1-phosphate .- Function :...
(CDase) enzymes on ceramide in the lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
. Sph can also be formed in the extracellular (outer leaflet) side of the plasma membrane by the action of neutral CDase enzyme. Sph then is either recycled back to ceramide or phosphorylated by one of the sphingosine kinase
Sphingosine kinase
Sphingosine kinase is a conserved lipid kinase that catalyzes formation Sphingosine-1-phosphate from the precursor sphingolipid sphingosine. Sphingolipid metabolites, such as ceramide, sphingosine and sphingosine-1-phosphate, are lipid second messengers involved in diverse cellular processes. ...
enzymes, SK1 and SK2. The product sphingosine-1-phosphate
Sphingosine-1-phosphate
Sphingosine-1-phosphate is a signaling sphingolipid. It is also referred to as a bioactive lipid mediator. Sphingolipids at large form a class of lipids characterized by a particular aliphatic aminoalcohol, which is sphingosine.-Production:...
(S1P) can be dephosphorylated in the ER to regenerate sphingosine
Sphingosine
Sphingosine is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, which forms a primary part of sphingolipids, a class of cell membrane lipids that include sphingomyelin, an important phospholipid.-Functions:...
by certain S1P phosphatase
Phosphatase
A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
enzymes within cells, where the salvaged Sph is recycled to ceramide
Ceramide
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
. Sphingosine
Sphingosine
Sphingosine is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, which forms a primary part of sphingolipids, a class of cell membrane lipids that include sphingomyelin, an important phospholipid.-Functions:...
is a single-chain lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
(usually 18 carbons in length), rendering it to have sufficient solubility in water. This explains its ability to move between membranes and to flip-flop across a membrane. Estimates conducted at physiological pH show that approximately 70% of sphingosine remains in membranes while the remaining 30% is water-soluble. Sph that is formed has sufficient solubility in the liquid found inside cells (cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
). Thus, Sph may come out of the lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
and move to the ER without the need for transport via proteins or membrane-enclosed sacs called vesicles
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
. However, its positive charge favors partitioning in lysosomes. It is proposed that the role of SK1 located near or in the lysosome is to ‘trap’ Sph via phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
.
It is important to note that since sphingosine exerts surfactant
Surfactant
Surfactants are compounds that lower the surface tension of a liquid, the interfacial tension between two liquids, or that between a liquid and a solid...
activity, it is one of the sphingolipids found at lowest cellular levels. The low levels of Sph and their increase in response to stimulation of cells, primarily by activation of ceramidase
Ceramidase
Ceramidase is an enzyme which cleaves fatty acids from ceramide, producing sphingosine which in turn is phosphorylated by a sphingosine kinase to form sphingosine-1-phosphate .- Function :...
by growth-inducing proteins such as platelet-derived growth factor
Platelet-derived growth factor
In molecular biology, platelet-derived growth factor is one of the numerous growth factors, or proteins that regulate cell growth and division. In particular, it plays a significant role in blood vessel formation , the growth of blood vessels from already-existing blood vessel tissue. Uncontrolled...
and insulin-like growth factor
Insulin-like growth factor
The insulin-like growth factors are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment...
, is consistent with its function as a second messenger. It was found that immediate hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
of only 3 to 10% of newly-generated ceramide
Ceramide
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
may double the levels of Sph. Treatment of HL60 cells (a type of leukemia cell line) by a plant-derived organic compound called phorbol
Phorbol
Phorbol is a natural, plant-derived organic compound. It is a member of the tigliane family of diterpenes. It was first isolated in 1934 as the hydrolysis product of croton oil, which is derived from the seeds of Croton tiglium. Phorbol's structure was determined in 1967...
ester increased Sph levels threefold, whereby the cells differentiated into white blood cells called macrophages. Treatment of the same cells by exogenous Sph caused apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. A specific protein kinase
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
phosphorylates 14-3-3, otherwise known as sphingosine-dependent protein kinase 1 (SDK1), only in the presence of Sph.
Sph is also known to interact with protein targets such as the protein kinase
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
H homologue (PKH) and the yeast protein kinase (YPK). These targets in turn mediate the effects of Sph and its related sphingoid bases, with known roles in regulating the actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
, endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
, the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
and apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. It is important to note however that the second messenger function of Sph is not yet established unambiguously.
Sphingosine-1-Phosphate
Sphingosine-1-phosphateSphingosine-1-phosphate
Sphingosine-1-phosphate is a signaling sphingolipid. It is also referred to as a bioactive lipid mediator. Sphingolipids at large form a class of lipids characterized by a particular aliphatic aminoalcohol, which is sphingosine.-Production:...
(S1P), like Sph, is composed of a single hydrophobic chain and has sufficient solubility to move between membranes. S1P is formed by phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of sphingosine
Sphingosine
Sphingosine is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, which forms a primary part of sphingolipids, a class of cell membrane lipids that include sphingomyelin, an important phospholipid.-Functions:...
by sphingosine kinase
Sphingosine kinase
Sphingosine kinase is a conserved lipid kinase that catalyzes formation Sphingosine-1-phosphate from the precursor sphingolipid sphingosine. Sphingolipid metabolites, such as ceramide, sphingosine and sphingosine-1-phosphate, are lipid second messengers involved in diverse cellular processes. ...
(SK). The phosphate group of the product can be detached (dephosphorylated) to regenerate sphingosine via S1P phosphatase
Phosphatase
A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
enzymes or S1P can be broken down by S1P lyase
Lyase
In biochemistry, a lyase is an enzyme that catalyzes the breaking of various chemical bonds by means other than hydrolysis and oxidation, often forming a new double bond or a new ring structure...
enzymes to ethanolamine phosphate and hexadecenal. Similar to Sph, its second messenger function is not yet clear. However, there is substantial evidence that implicates S1P to cell survival, cell migration
Cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
, and inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
. Certain growth-inducing proteins such as platelet-derived growth factor
Platelet-derived growth factor
In molecular biology, platelet-derived growth factor is one of the numerous growth factors, or proteins that regulate cell growth and division. In particular, it plays a significant role in blood vessel formation , the growth of blood vessels from already-existing blood vessel tissue. Uncontrolled...
(PDGF), insulin-like growth factor
Insulin-like growth factor
The insulin-like growth factors are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment...
(IGF) and vascular endothelial growth factor
Vascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
(VEGF) promote the formation of SK enzymes, leading to increased levels of S1P. Other factors that induce SK include cellular communication molecules called cytokines, such as tumor necrosis factor α (TNFα) and interleukin-1 (IL-1), hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
or lack of oxygen supply in cells, oxidized low-density lipoproteins (oxLDL) and several immune complexes.
S1P is probably formed at the inner leaflet of the plasma membrane in response to TNFα and other receptor activity-altering compounds called agonists. S1P, being present in low nanomolar concentrations in the cell, has to interact with high-affinity receptors that are capable of sensing their low levels. So far, the only identified receptors for S1P are the high-affinity G protein-coupled receptors (GPCRs), also known as S1P receptors (S1PRs). S1P is required to reach the extracellular side (outer leaflet) of the plasma membrane to interact with S1PRs and launch typical GPCR signaling pathways. However, the zwitterionic headgroup of S1P makes it unlikely to flip-flop spontaneously. To overcome this difficulty, the ATP-binding cassette (ABC) transporter C1 (ABCC1) serves as the "exit door" for S1P. On the other hand, the cystic fibrosis transmembrane regulator (CFTR) serves as the means of entry for S1P into the cell. In contrast to its low intracellular concentration, S1P is found in high nanomolar concentrations in serum
Blood serum
In blood, the serum is the component that is neither a blood cell nor a clotting factor; it is the blood plasma with the fibrinogens removed...
where it is bound to albumin
Albumin
Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...
and lipoproteins. Inside the cell, S1P can induce calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
release independent of the S1PRs—the mechanism of which remains unknown. To date, the intracellular molecular targets for S1P are still unidentified.
The SK1-S1P pathway has been extensively studied in relation to cytokine action, with multiple functions connected to effects of TNFα and IL-1 favoring inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
. Studies show that knockdown of key enzymes such as S1P lyase
Lyase
In biochemistry, a lyase is an enzyme that catalyzes the breaking of various chemical bonds by means other than hydrolysis and oxidation, often forming a new double bond or a new ring structure...
and S1P phosphatase increased prostaglandin
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
production, parallel to increase of S1P levels. This strongly suggests that S1P is the mediator of SK1 action and not subsequent compounds. Research done on endothelial and smooth muscle
Smooth muscle
Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...
cells is consistent to the hypothesis that S1P has a crucial role in regulating endothelial cell growth, and movement. Recent work on a sphingosine
Sphingosine
Sphingosine is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, which forms a primary part of sphingolipids, a class of cell membrane lipids that include sphingomyelin, an important phospholipid.-Functions:...
analogue, FTY270, demonstrates its ability to act as a potent compound that alters the activity of S1P receptors (agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
). FTY270 was further verified in clinical tests to have roles in immune modulation, such as that on multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
. This highlights the importance of S1P in the regulation of lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
function and immunity
Immunity (medical)
Immunity is a biological term that describes a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide...
. Most of the studies on S1P are used to further understand diseases such as cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
and inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
, diabetes, immune function and neurodegenerative disorders.
Glucosylceramide
Glucosylceramides (GluCer) are the most widely distributed glycosphingolipidsGlycosphingolipids
Glycosphingolipids are a subtype of glycolipids containing the amino alcohol sphingosine. They include:* Cerebrosides* Gangliosides* Globosides...
in cells serving as precursors
Precursor (chemistry)
In chemistry, a precursor is a compound that participates in the chemical reaction that produces another compound. In biochemistry, the term "precursor" is used more specifically to refer to a chemical compound preceding another in a metabolic pathway....
for the formation of over 200 known glycosphingolipids. GluCer is formed by the glycosylation of ceramide in an organelle called Golgi
Golgi
Golgi may refer to:*Camillo Golgi , Italian physician and scientist after which the following terms are named:**Golgi apparatus , an organelle in the eukaryotic cell...
via enzymes called glucosylceramide synthase (GCS) or by the breakdown of complex glycosphingolipids
Glycosphingolipids
Glycosphingolipids are a subtype of glycolipids containing the amino alcohol sphingosine. They include:* Cerebrosides* Gangliosides* Globosides...
(GSLs) through the action of specific hydrolase
Hydrolase
In biochemistry, a hydrolase is an enzyme that catalyzes the hydrolysis of a chemical bond. For example, an enzyme that catalyzed the following reaction is a hydrolase:-Nomenclature:...
enzymes. In turn, certain β-glucosidases hydrolyse these lipids to regenerate ceramide. GluCer appears to be synthesized in the inner leaflet of the Golgi
Golgi
Golgi may refer to:*Camillo Golgi , Italian physician and scientist after which the following terms are named:**Golgi apparatus , an organelle in the eukaryotic cell...
. Studies show that GluCer has to flip to the inside of the Golgi or transfer to the site of GSL synthesis to initiate the synthesis of complex GSLs. Transferring to the GSL synthesis site is done with the help of a transport protein known as four phosphate adaptor protein 2 (FAPP2) while the flipping to the inside of the Golgi is made possible by the ABC transporter P-glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
, also known as the multi-drug resistance 1 transporter (MDR1). GluCer is implicated in post-Golgi trafficking and drug resistance particularly to chemotherapeutic agents. For instance, a study demonstrated a correlation between cellular drug resistance
Drug resistance
Drug resistance is the reduction in effectiveness of a drug such as an antimicrobial or an antineoplastic in curing a disease or condition. When the drug is not intended to kill or inhibit a pathogen, then the term is equivalent to dosage failure or drug tolerance. More commonly, the term is used...
and modifications in GluCer metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
.
In addition to their role as building blocks of biological membranes, glycosphingolipids
Glycosphingolipids
Glycosphingolipids are a subtype of glycolipids containing the amino alcohol sphingosine. They include:* Cerebrosides* Gangliosides* Globosides...
have long attracted attention because of their supposed involvement in cell growth, differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
, and formation of tumors. The production of GluCer from Cer was found to be important in the growth of neurons or brain cells. On the other hand, pharmacological inhibition
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
of GluCer synthase is being considered a technique to avoid insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
.
Ceramide-1-Phosphate
Ceramide-1-phosphate (C1P) is formed by the action of ceramide kinaseCeramide kinase
In enzymology, a ceramide kinase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are ATP and ceramide, whereas its two products are ADP and ceramide 1-phosphate....
(CK) enzymes on Cer. C1P carry ionic charge at neutral pH and contain two hydrophobic chains making it relatively insoluble in aqueous environment. Thus, C1P reside in the organelle where it was formed and is unlikely to spontaneously flip-flop across membrane bilayers.
C1P activate phospholipase A2
Phospholipase A2
Phospholipases A2 are enzymes that release fatty acids from the second carbon group of glycerol. This particular phospholipase specifically recognizes the sn-2 acyl bond of phospholipids and catalytically hydrolyzes the bond releasing arachidonic acid and lysophospholipids...
and is found, along with CK, to be a mediator of arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
released in cells in response to a protein called interleukin
Interleukin
Interleukins are a group of cytokines that were first seen to be expressed by white blood cells . The term interleukin derives from "as a means of communication", and "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes"...
-1β (IL-1β) and a lipid-soluble molecule that transports calcium ions (Ca2+) across the bilayer, also known as calcium ionophore
Ionophore
An ionophore is a lipid-soluble molecule usually synthesized by microorganisms to transport ions across the lipid bilayer of the cell membrane...
. C1P was also previously reported to encourage cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
(mitogenic) in fibroblasts, block apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
by inhibiting acid SMase in white blood cells within tissues (macrophages) and increase intracellular free calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
concentrations in thyroid
Thyroid
The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
cells. C1P also has known roles in vesicular
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
trafficking, cell survival, phagocytosis ("cell eating") and macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
degranulation
Degranulation
Degranulation is a cellular process that releases antimicrobial cytotoxic molecules from secretory vesicles called granules found inside some cells...
.
Phosphatidylinositol bisphosphate (PIP2) Second Messenger Systems
A general second messenger systemSecond messenger system
Second messengers are molecules that relay signals from receptors on the cell surface to target molecules inside the cell, in the cytoplasm or nucleus. They relay the signals of hormones like epinephrine , growth factors, and others, and cause some kind of change in the activity of the cell...
mechanism can be broken down into four steps. First, the agonist activates a membrane-bound receptor. Second, the activated G-protein produces a primary effector. Third, the primary effect stimulates the second messenger synthesis. Fourth, the second messenger activates a certain cellular process.
The G-protein coupled receptors for the PIP2 messenger system produces two effectors, phospholipase C
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
(PLC) and phosphoinositide 3-kinase
Phosphoinositide 3-kinase
Phosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
(PI3K). PLC as an effector produces two different second messengers, inositol triphosphate
Inositol triphosphate
Inositol trisphosphate or inositol 1,4,5-trisphosphate , together with diacylglycerol , is a secondary messenger molecule used in signal transduction and lipid signaling in biological cells. While DAG stays inside the membrane, IP3 is soluble and diffuses through the cell...
(IP3) and Diacylglycerol (DAG).
IP3 is soluble and diffuses freely into the cytoplasm. As a second messenger, it is recognised by the inositol triphosphate receptor (IP3R), a Ca2+ channel in the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
(ER) membrane, which stores intracellular Ca2+. The binding of IP3 to IP3R releases Ca2+ from the ER into the normally Ca2+-poor cytoplasm, which then triggers various events of Ca2+ signaling. Specifically in blood vessels, the increase in Ca2+ concentration from IP3 releases nitric oxide, which then diffuses into the smooth muscle tissue and causes constrictions.
DAG remains bound to the membrane by its fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
"tails" where it recruits and activates both conventional and novel members of the protein kinase C
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
family. Thus, both IP3 and DAG contribute to activation of PKCs.
Phosphoinositide 3-kinase
Phosphoinositide 3-kinase
Phosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
(PI3K) as an effector phosphorylates phosphatidylinositol bisphosphate
Phosphatidylinositol bisphosphate
Phosphatidylinositol bisphosphate may refer to:* Phosphatidylinositol -bisphosphate* Phosphatidylinositol -bisphosphate* Phosphatidylinositol -bisphosphate...
(PIP2) to produce phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol -triphosphate , abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases phosphorylation on phosphatidylinositol -bisphosphate .-Discovery:...
(PIP3). PIP3 has been shown to activate protein kinase B, increase binding to extracellular proteins and ultimately enhance cell survival.
Lysophosphatidic acid (LPA)
LPALysophosphatidic acid
Lysophosphatidic acid is a phospholipid derivative that can act as a signaling molecule.-Function:LPA acts as a potent mitogen due to its activation of three high-affinity G-protein-coupled receptors called LPA1, LPA2, and LPA3...
is the result of phospholipase A2
Phospholipase A2
Phospholipases A2 are enzymes that release fatty acids from the second carbon group of glycerol. This particular phospholipase specifically recognizes the sn-2 acyl bond of phospholipids and catalytically hydrolyzes the bond releasing arachidonic acid and lysophospholipids...
action on phosphatidic acid. The SN-1 position can contain either an ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
bond or an ether
Ether
Ethers are a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R'. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...
bond, with ether
Ether
Ethers are a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R'. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...
LPA being found at elevated levels in certain cancers. LPA binds the high-affinity G-protein coupled receptors LPA1
Lysophospholipid receptor
The lysophospholipid receptor group are members of the G protein-coupled receptor family of integral membrane proteins that are important for lipid signaling. In humans, there are eight LPL receptors, each encoded by a separate gene...
, LPA2
Lysophospholipid receptor
The lysophospholipid receptor group are members of the G protein-coupled receptor family of integral membrane proteins that are important for lipid signaling. In humans, there are eight LPL receptors, each encoded by a separate gene...
, and LPA3
Lysophospholipid receptor
The lysophospholipid receptor group are members of the G protein-coupled receptor family of integral membrane proteins that are important for lipid signaling. In humans, there are eight LPL receptors, each encoded by a separate gene...
(also known as EDG2
Lysophospholipid receptor
The lysophospholipid receptor group are members of the G protein-coupled receptor family of integral membrane proteins that are important for lipid signaling. In humans, there are eight LPL receptors, each encoded by a separate gene...
, EDG4
Lysophospholipid receptor
The lysophospholipid receptor group are members of the G protein-coupled receptor family of integral membrane proteins that are important for lipid signaling. In humans, there are eight LPL receptors, each encoded by a separate gene...
, and EDG7
Lysophospholipid receptor
The lysophospholipid receptor group are members of the G protein-coupled receptor family of integral membrane proteins that are important for lipid signaling. In humans, there are eight LPL receptors, each encoded by a separate gene...
, respectively).
Sphingosine-1-phosphate (S1P)
S1PS1P
S1P may refer to:* Site-1 Protease* Sphingosine-1-Phosphate...
is present at high concentrations in plasma and secreted locally at elevated concentrations at sites of inflammation. It is formed by the regulated phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of sphingosine
Sphingosine
Sphingosine is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, which forms a primary part of sphingolipids, a class of cell membrane lipids that include sphingomyelin, an important phospholipid.-Functions:...
. It acts through five dedicated high-affinity G-protein coupled receptors, S1P1
Lysophospholipid receptor
The lysophospholipid receptor group are members of the G protein-coupled receptor family of integral membrane proteins that are important for lipid signaling. In humans, there are eight LPL receptors, each encoded by a separate gene...
- S1P5
Lysophospholipid receptor
The lysophospholipid receptor group are members of the G protein-coupled receptor family of integral membrane proteins that are important for lipid signaling. In humans, there are eight LPL receptors, each encoded by a separate gene...
. Interestingly, targeted deletion of S1P1 results in lethality in mice and deletion of S1P2 results in seizures and deafness. Additionally, a mere 3- to 5-fold elevation in serum S1P concentrations induces sudden cardiac death by an S1P3
Lysophospholipid receptor
The lysophospholipid receptor group are members of the G protein-coupled receptor family of integral membrane proteins that are important for lipid signaling. In humans, there are eight LPL receptors, each encoded by a separate gene...
-receptor specific mechanism.
Platelet activating factor (PAF)
PAF is a potent activator of platelet aggregation, inflammation, and anaphylaxis. It is similar to the ubiquitous membrane phospholipidPhospholipid
Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...
phosphatidylcholine
Phosphatidylcholine
Phosphatidylcholines are a class of phospholipids that incorporate choline as a headgroup.They are a major component of biological membranes and can be easily obtained from a variety of readily available sources such as egg yolk or soy beans from which they are mechanically extracted or chemically...
except that it contains an acetyl
Acetyl
In organic chemistry, acetyl is a functional group, the acyl with chemical formula COCH3. It is sometimes represented by the symbol Ac . The acetyl group contains a methyl group single-bonded to a carbonyl...
-group in the SN-2 position and the SN-1 position contains an ether
Ether
Ethers are a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R'. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...
-linkage. PAF signals through a dedicated G-protein coupled receptor, PAFR and is inactivated by PAF acetylhydrolase.
Endocannabinoids
The endogenous cannabinoidsCannabinoids
Cannabinoids are a class of chemical compounds that include the phytocannabinoids , and chemical compounds that mimic the actions of phytocannabinoids or have a similar structure...
, or endocannabinoids, are endogenous lipids that activate cannabinoid receptors. The first such lipid to be isolated was anandamide
Anandamide
Anandamide, also known as N-arachidonoylethanolamide or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways...
which is the arachidonoyl amide
Amide
In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...
of ethanolamine
Ethanolamine
Ethanolamine, also called 2-aminoethanol or monoethanolamine , is an organic chemical compound that is both a primary amine and a primary alcohol . Like other amines, monoethanolamine acts as a weak base...
. Anandamide is formed via enzymatic release from N-arachidonoyl phosphatidylethanolamine
Phosphatidylethanolamine
Phosphatidylethanolamine is a lipid found in biological membranes. It is synthesized by the addition of CDP-ethanolamine to diglyceride, releasing CMP. S-adenosyl methionine can subsequently methylate the amine of phosphatidyl ethanolamine to yield phosphatidyl choline.Cephalin is a phospholipid,...
by enzymes which have not yet been delineated. It activates both the CB1 receptor, found primarily in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
, and the CB2 receptor which is found primarily in lymphocytes and the periphery. It is found at very low levels (nM) in most tissues and is inactivated by the fatty acid amide hydrolase. Subsequently, another endocannabinoid was isolated, 2-arachidonoylglycerol
2-Arachidonoylglycerol
2-Arachidonoylglycerol is an endocannabinoid, an endogenous agonist of the CB1 receptor. It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is present at relatively high levels in the central nervous system, with cannabinoid neuromodulatory effects. It has been...
, which is produced when phospholipase C
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
releases diacylglycerol
Diglyceride
A diglyceride, or a diacylglycerol , is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages....
which is then converted to 2-AG by diacylglycerol lipase
Diacylglycerol lipase
Diacylglycerol lipase, also known as DAG lipase, DAGL or DGL, is a key enzyme in the biosynthesis of the endocannabinoid 2-arachidonoylglycerol. It catalyzes the hydrolysis of diacylglycerol, releasing a free fatty acid and monoacylglycerol....
. 2-AG can also activate both cannabinoid receptors and is inactivated by monoacylglycerol lipase
Monoacylglycerol lipase
Monoacylglycerol lipase, also known as MAG lipase, MAGL, MGL or MGLL is a protein that, in humans, is encoded by the MGLL gene. MAGL is a 33-kDa, membrane-associated member of the serine hydrolase superfamily and contains the classical GXSXG consensus sequence common to most serine hydrolases...
. It is present at approximately 100-times the concentration of anandamide
Anandamide
Anandamide, also known as N-arachidonoylethanolamide or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways...
in most tissues.
Elevations in either of these lipids causes analgesia and anti-inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
but the precise roles played by these two endocannabinoids are still vague and intensive research into their function, metabolism, and regulation is ongoing.
Prostaglandins
ProstaglandinProstaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
s are formed through oxidation of arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
by cyclooxygenase
Cyclooxygenase
Cyclooxygenase is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain...
s and other prostaglandin synthases. There are currently nine known G-protein coupled receptors (eicosanoid receptor
Eicosanoid receptor
An eicosanoid receptor is an integral membrane protein which detects the presence of eicosanoid signaling molecules. Most, though not all, are G protein-coupled receptors...
s) that largely mediate prostaglandin physiology (although some prostaglandins activate nuclear receptor
Nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...
s, see below).
Retinol derivatives
Retinaldehyde is a retinolRetinol
Retinol is one of the animal forms of vitamin A. It is a diterpenoid and an alcohol. It is convertible to other forms of vitamin A, and the retinyl ester derivative of the alcohol serves as the storage form of the vitamin in animals....
(vitamin A
Vitamin A
Vitamin A is a vitamin that is needed by the retina of the eye in the form of a specific metabolite, the light-absorbing molecule retinal, that is necessary for both low-light and color vision...
) derivative responsible for vision. It binds rhodopsin
Rhodopsin
Rhodopsin, also known as visual purple, is a biological pigment of the retina that is responsible for both the formation of the photoreceptor cells and the first events in the perception of light. Rhodopsins belong to the G-protein coupled receptor family and are extremely sensitive to light,...
, a well-characterized GPCR that binds all-cis retinal
Retinal
Retinal, also called retinaldehyde or vitamin A aldehyde, is one of the many forms of vitamin A . Retinal is a polyene chromophore, and bound to proteins called opsins, is the chemical basis of animal vision...
in its inactive state. Upon photoisomerization by a photon
Photon
In physics, a photon is an elementary particle, the quantum of the electromagnetic interaction and the basic unit of light and all other forms of electromagnetic radiation. It is also the force carrier for the electromagnetic force...
the cis-retinal is converted to trans-retinal causing activation of rhodopsin
Rhodopsin
Rhodopsin, also known as visual purple, is a biological pigment of the retina that is responsible for both the formation of the photoreceptor cells and the first events in the perception of light. Rhodopsins belong to the G-protein coupled receptor family and are extremely sensitive to light,...
which ultimately leads to depolarization
Depolarization
In biology, depolarization is a change in a cell's membrane potential, making it more positive, or less negative. In neurons and some other cells, a large enough depolarization may result in an action potential...
of the neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
thereby enabling visual perception
Visual perception
Visual perception is the ability to interpret information and surroundings from the effects of visible light reaching the eye. The resulting perception is also known as eyesight, sight, or vision...
.
Steroid Hormones
This large and diverse class of steroids are biosynthesized from isoprenoids and structurally resemble cholesterolCholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
. Mammalian steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestagens.
Retinoic acid
RetinolRetinol
Retinol is one of the animal forms of vitamin A. It is a diterpenoid and an alcohol. It is convertible to other forms of vitamin A, and the retinyl ester derivative of the alcohol serves as the storage form of the vitamin in animals....
(vitamin A
Vitamin A
Vitamin A is a vitamin that is needed by the retina of the eye in the form of a specific metabolite, the light-absorbing molecule retinal, that is necessary for both low-light and color vision...
) can be metabolized to retinoic acid
Retinoic acid
Retinoic acid is a metabolite of vitamin A that mediates the functions of vitamin A required for growth and development. Retinoic acid is required in chordate animals which includes all higher animals from fishes to humans...
which activates nuclear receptors such as the RAR
Retinoic acid receptor
The retinoic acid receptor is a type of nuclear receptor that is activated by both all-trans retinoic acid and 9-cis retinoic acid. There are three retinoic acid receptors , RAR-alpha, RAR-beta, and RAR-gamma, encoded by the , , genes, respectively...
to control differentiation and proliferation of many types of cells during development.
Prostaglandins
The majority of prostaglandinProstaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
signaling occurs via GPCRs (see above) although certain prostaglandin
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
s activate nuclear receptors in the PPAR family. (See article eicosanoid receptor
Eicosanoid receptor
An eicosanoid receptor is an integral membrane protein which detects the presence of eicosanoid signaling molecules. Most, though not all, are G protein-coupled receptors...
s for more information).
See also
- Allostery
- Cell signalingCell signalingCell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue...
- Lysophospholipid receptorLysophospholipid receptorThe lysophospholipid receptor group are members of the G protein-coupled receptor family of integral membrane proteins that are important for lipid signaling. In humans, there are eight LPL receptors, each encoded by a separate gene...
s - Protein dynamics
- List of signaling molecule types