Lipid signaling, broadly defined, refers to any biological

cell signaling In biology, cell signaling (cell signalling in British English) is the Biological process, process by which a Cell (biology), cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all Cell (biol ...

event involving a

lipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...

messenger that binds a protein target, such as a

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

phosphatase In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid Ester, monoester into a phosphate ion and an Alcohol (chemistry), alcohol. Because a phosphatase enzyme catalysis, catalyzes the hydrolysis of its Substrate ...

, 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 Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin. All monoamines are ...

neurotransmission Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron ...

) because lipids can freely

diffuse Diffusion is the net movement of anything (for example, atoms, ions, molecules, energy) generally from a region of higher concentration to a region of lower concentration. Diffusion is driven by a gradient in Gibbs free energy or chemical p ...

through

membranes A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. B ...

(''see

osmosis Osmosis (, ) is the spontaneous net movement or diffusion of solvent molecules through a selectively permeable membrane, selectively-permeable membrane from a region of high water potential (region of lower solute concentration) to a region of ...

''). One consequence of this is that lipid messengers cannot be stored in

vesicles Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle In a neuron, synaptic vesicles (or neurotransmitter vesicles) s ...

prior to release and so are often

biosynthesized Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme- catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthesis) serve ...

"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.

Sphingolipid second messengers

Ceramide

Ceramide Ceramides are a family of waxy lipid molecules. A ceramide is composed of sphingosine and a fatty acid joined by an amide bond. Ceramides are found in high concentrations within the cell membrane of Eukaryote, eukaryotic cells, since they are co ...

(Cer) can be generated by the breakdown of

sphingomyelin Sphingomyelin (SPH, ) 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 phosphocholine and ceramide, or a phosphoethanolamine hea ...

(SM) by

sphingomyelinase Sphingomyelin phosphodiesterase (EC 3.1.4.12, also known as neutral sphingomyelinase, sphingomyelinase, or SMase; systematic name sphingomyelin cholinephosphohydrolase) is a hydrolase enzyme that is involved in sphingolipid metabolism reactions. ...

s (SMases), which are

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

s that hydrolyze the

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 and choline into phosphocholine and ADP. Phosphocholine is a molecule ...

group from the

sphingosine Sphingosine (2-amino-4-trans-octadecene-1,3-diol) 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 phosphol ...

backbone. Alternatively, this

-derived

(

sphingolipid Sphingolipids are a class of lipids containing a backbone of sphingoid bases, which are a set of aliphatic amino alcohols that includes sphingosine. They were discovered in brain extracts in the 1870s and were named after the mythological sp ...

) can be synthesized from scratch (''de novo'') by the enzymes serine palmitoyl transferase (SPT) and

ceramide Ceramides are a family of waxy lipid molecules. A ceramide is composed of sphingosine and a fatty acid joined by an amide bond. Ceramides are found in high concentrations within the cell membrane of Eukaryote, eukaryotic cells, since they are co ...

synthase In biochemistry, a synthase is an enzyme that catalyses a synthesis process. Note that, originally, biochemical nomenclature distinguished synthetases and synthases. Under the original definition, synthases do not use energy from nucleoside trip ...

organelles In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' th ...

such as the

endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

(ER) and possibly, in the

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

-associated membranes (MAMs) and the perinuclear membranes. Being located in the metabolic hub, ceramide leads to the formation of other

sphingolipids Sphingolipids are a class of lipids containing a backbone of sphingoid bases, which are a set of aliphatic amino alcohols that includes sphingosine. They were discovered in brain extracts in the 1870s and were named after the mythological sphi ...

, with the C1

hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...

(-OH) group as the major site of modification. A sugar can be attached to

(glycosylation) through the action of the enzymes, glucosyl or galactosyl

synthases. Ceramide can also be broken down by enzymes called ceramidases, leading to the formation of

, Moreover, a phosphate group can be attached to ceramide (phosphorylation) by the enzyme,

. It is also possible to regenerate sphingomyelin from ceramide by accepting a

headgroup from

phosphatidylcholine Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can easily be obtained from a variety of readily available sources, such as egg yolk or soyb ...

(PC) by the action of an enzyme called

. The latter process results in the formation of

diacylglycerol A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. Diglycerides are n ...

(DAG) from PC.

contains two

hydrophobic In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, thu ...

("water-fearing") chains and a neutral headgroup. Consequently, it has limited solubility in water and is restricted within the

organelle In cell biology, an organelle is a specialized subunit, usually within a cell (biology), cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as Organ (anatomy), organs are to th ...

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 Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...

). However,

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 A signal is both the process and the result of transmission of data over some media accomplished by embedding some variation. Signals are important in multiple subject fields including signal processing, information theory and biology. ...

functions of ceramide because it is known that

generated by acidic SMase enzymes in the outer leaflet of an organelle membrane may have different roles compared to

that is formed in the inner leaflet by the action of neutral SMase enzymes.

mediates many cell-stress responses, including the regulation of programmed cell death (

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

) and cell aging (

senescence Senescence () or biological aging is the gradual deterioration of Function (biology), functional characteristics in living organisms. Whole organism senescence involves an increase in mortality rate, death rates or a decrease in fecundity with ...

). Numerous research works have focused interest on defining the direct

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

targets of action of ceramide. These include enzymes called

-activated Ser-Thr

phosphatases In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid monoester into a phosphate ion and an alcohol. Because a phosphatase enzyme catalyzes the hydrolysis of its substrate, it is a subcategory of hydrolases. Pho ...

(CAPPs), such as

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 Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...

α (TNFα) and

palmitate Palmitic acid (hexadecanoic acid in IUPAC nomenclature) is a fatty acid with a 16-carbon chain. It is the most common saturated fatty acid found in animals, plants and microorganisms.Gunstone, F. D., John L. Harwood, and Albert J. Dijkstra. The Li ...

induce the ceramide-dependent removal of a phosphate group (dephosphorylation) of the

retinoblastoma Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common primary malignant intraocular cancer in children, and 80% of retinoblastoma cas ...

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

product RB and the enzymes,

protein kinases A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a fun ...

B ( AKT protein family) and C α (PKB and PKCα). Moreover, there is also sufficient evidence which implicates

to the activation of the kinase suppressor of Ras (KSR), PKCζ, and cathepsin D. Cathepsin D has been proposed as the main target for

formed in organelles called

lysosome A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...

s, making lysosomal acidic SMase enzymes one of the key players in the mitochondrial pathway of

. Ceramide was also shown to activate PKCζ, implicating it to the

inhibition Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransm ...

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 Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) in a standard regimen. Chemotherapy may be given with a cura ...

such as

daunorubicin Daunorubicin, also known as daunomycin, is a chemotherapy medication used to treat cancer. Specifically it is used for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and Kaposi's sarcoma. I ...

and

etoposide Etoposide, sold under the brand name Vepesid among others, is a chemotherapy medication used for the treatments of a number of types of cancer including testicular cancer, lung cancer, lymphoma, leukemia, neuroblastoma, and ovarian cancer. It is ...

enhance the ''de novo'' synthesis of

in studies done on mammalian cells. The same results were found for certain inducers of

particularly stimulators of

receptors Receptor may refer to: *Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds ...

in a class of lymphocytes (a type of white blood cell) called

B-cell B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...

s. Regulation of the ''de novo'' synthesis of ceramide by

may have a key role in

diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...

and the

metabolic syndrome Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Metabolic syndro ...

. Experimental evidence shows that there is substantial increase of

levels upon adding

accumulation activates PP2A and the subsequent dephosphorylation and inactivation of AKT, a crucial mediator in metabolic control and

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

. This results in a substantial decrease in

responsiveness (i.e. to glucose) and in the death of insulin-producing cells in the pancreas called

islets of Langerhans The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% o ...

. Inhibition of ceramide synthesis in mice via drug treatments or gene-knockout techniques prevented insulin resistance induced by

fatty acids In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...

glucocorticoids Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebra ...

obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

. An increase in ''in vitro'' activity of acid SMase has been observed after applying multiple stress stimuli such as

ultraviolet Ultraviolet radiation, also known as simply UV, is electromagnetic radiation of wavelengths of 10–400 nanometers, shorter than that of visible light, but longer than X-rays. UV radiation is present in sunlight and constitutes about 10% of ...

(UV) and ionizing radiation, binding of death receptors and

chemotherapeutic agents Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) in a standard regimen. Chemotherapy may be given with a cura ...

such as

platinum Platinum is a chemical element; it has Symbol (chemistry), symbol Pt and atomic number 78. It is a density, dense, malleable, ductility, ductile, highly unreactive, precious metal, precious, silverish-white transition metal. Its name origina ...

histone deacetylase inhibitor Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that enzyme inhibitor, inhibit histone deacetylases. Since acetylation of histones, deacetylation of histones produces transcriptionally silenced heterochromatin ...

s and

paclitaxel Paclitaxel, sold under the brand name Taxol among others, is a chemotherapy medication used to treat ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, and pancreatic cancer. It is administered b ...

. In some studies, SMase activation results to its transport to the

plasma membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

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 Phosphatidylinositol or inositol phospholipid is a biomolecule. It was initially called "inosite" when it was discovered by Léon Maquenne and Johann Joseph von Scherer in the late 19th century. It was discovered in bacteria but later also found ...

phosphates, hinting its potential regulation via

phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

, a step of the ceramide metabolism that can be enzymatically regulated by

and

, and by

inositol In biochemistry, medicine, and related sciences, inositol generally refers to ''myo''-inositol (formerly ''meso''-inositol), the most important stereoisomer of the chemical compound cyclohexane-1,2,3,4,5,6-hexol. Its elemental formula, formula is ...

metabolic pathways. Up to date, there are at least 26 distinct enzymes with varied subcellular localizations, that act on ceramide as either a

substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (aquatic environment), the earthy material that exi ...

or product. Regulation of ceramide levels can therefore be performed by one of these

enzymes An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as pro ...

in distinct organelles by particular mechanisms at various times.

Sphingosine

Sphingosine Sphingosine (2-amino-4-trans-octadecene-1,3-diol) 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 phosphol ...

(Sph) is formed by the action of

ceramidase Ceramidase (, ''acylsphingosine deacylase'', ''glycosphingolipid ceramide deacylase'') is an enzyme which cleaves fatty acids from ceramide, producing sphingosine (SPH) which in turn is phosphorylated by a sphingosine kinase to form sphingosi ...

(CDase) enzymes on ceramide in the

. Sph can also be formed in the extracellular (outer leaflet) side of the

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

by certain S1P

enzymes within cells, where the salvaged Sph is recycled to

is a single-chain

(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 The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

). Thus, Sph may come out of the

and move to the ER without the need for transport via proteins or membrane-enclosed sacs called

. However, its positive charge favors partitioning in

lysosomes A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...

. It is proposed that the role of SK1 located near or in the lysosome is to ‘trap’ Sph via

.Hannun and Obeid (2008) Since sphingosine exerts

surfactant Surfactants are chemical compounds that decrease the surface tension or interfacial tension between two liquids, a liquid and a gas, or a liquid and a solid. The word ''surfactant'' is a Blend word, blend of "surface-active agent", coined in ...

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

by growth-inducing proteins such as

platelet-derived growth factor Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing bloo ...

and

insulin-like growth factor The insulin-like growth factors (IGFs) are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment. This complex system (often referred to as the IGF ...

, is consistent with its function as a

second messenger Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form of cell signaling, encompassing both first m ...

. It was found that immediate

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

of only 3 to 10% of newly generated

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 is a natural, plant-derived organic compound. It is a member of the tigliane family of terpene, diterpenes. Phorbol was first isolated in 1934 via the hydrolysis of croton oil, which is derived from the seeds of the purging croton, ''Crot ...

ester increased Sph levels threefold, whereby the cells differentiated into white blood cells called

macrophages Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

. Treatment of the same cells by exogenous Sph caused

. A specific

protein kinase A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them ( phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a f ...

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

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 is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ...

cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...

endocytosis Endocytosis is a cellular process in which Chemical substance, substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a Vesicle (biology and chem ...

, the

cell cycle The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...

and

. It is important to note however that the

function of Sph is not yet established unambiguously.

Sphingosine-1-Phosphate

Sphingosine-1-phosphate (S1P), like Sph, is composed of a single hydrophobic chain and has sufficient solubility to move between membranes. S1P is formed by

by sphingosine kinase (SK). The phosphate group of the product can be detached (dephosphorylated) to regenerate sphingosine via S1P

enzymes or S1P can be broken down by S1P

lyase In biochemistry, a lyase is an enzyme that catalyzes the breaking (an elimination reaction) of various chemical bonds by means other than hydrolysis (a substitution reaction) and oxidation Redox ( , , reduction–oxidation or oxidatio ...

enzymes to ethanolamine phosphate and hexadecenal. Similar to Sph, its

function is not yet clear. However, there is substantial evidence that implicates S1P to cell survival,

cell migration Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryogenesis, embryonic development, wound healing and immune system, immune responses all require the orchestrated movemen ...

, and

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

. Certain growth-inducing proteins such as

(PDGF),

(IGF) and

vascular endothelial growth factor Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors ...

(VEGF) promote the formation of SK enzymes, leading to increased levels of S1P. Other factors that induce SK include cellular communication molecules called

cytokines Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

, such as

tumor necrosis factor α Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...

(TNFα) and

interleukin-1 The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults. Discovery Discovery of these cytokines began with studies on t ...

(IL-1), hypoxia or lack of oxygen supply in cells, oxidized low-density

lipoproteins A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, sur ...

(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 An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agon ...

. 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 G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large protein family, group of evoluti ...

(GPCRs), also known as S1P receptors (S1PRs). S1P is required to reach the extracellular side (outer leaflet) of the

to interact with S1PRs and launch typical GPCR

pathways. However, the

zwitterion In chemistry, a zwitterion ( ; ), also called an inner salt or dipolar ion, is a molecule that contains an equal number of positively and negatively charged functional groups. : (1,2- dipolar compounds, such as ylides, are sometimes excluded from ...

ic 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 Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...

and

. Inside the cell, S1P can induce

calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...

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 Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...

and IL-1 favoring

. Studies show that knockdown of key enzymes such as S1P

and S1P phosphatase increased

prostaglandin Prostaglandins (PG) are a group of physiology, physiologically active lipid compounds called eicosanoids that have diverse hormone-like effects in animals. Prostaglandins have been found in almost every Tissue (biology), tissue in humans and ot ...

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 The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the res ...

and

smooth muscle Smooth muscle is one of the three major types of vertebrate muscle tissue, the others being skeletal and cardiac muscle. It can also be found in invertebrates and is controlled by the autonomic nervous system. It is non- striated, so-called bec ...

cells is consistent to the hypothesis that S1P has a crucial role in regulating

cell growth, and movement. Recent work on a

analogue, FTY270, demonstrates its ability to act as a potent compound that alters the activity of S1P receptors (

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

). FTY270 was further verified in clinical tests to have roles in immune modulation, such as that on

multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...

. This highlights the importance of S1P in the regulation of

lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), an ...

function and

immunity Immunity may refer to: Medicine * Immunity (medical), resistance of an organism to infection or disease * ''Immunity'' (journal), a scientific journal published by Cell Press Biology * Immune system Engineering * Radiofrequence immunity ...

. Most of the studies on S1P are used to further understand diseases such as

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

arthritis Arthritis is a general medical term used to describe a disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, Joint effusion, swelling, and decreased range of motion of ...

and

immune In biology, immunity is the state of being insusceptible or resistant to a noxious agent or process, especially a pathogen or infectious disease. Immunity may occur naturally or be produced by prior exposure or immunization. Innate and adaptive ...

function and

neurodegenerative disorders A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, mul ...

Glucosylceramide

Glucosylceramides (GluCer) are the most widely distributed glycosphingolipids 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 In biochemistry, hydrolases constitute a class of enzymes that commonly function as biochemical catalysts that use water to break a chemical bond: :\ce \quad \xrightarrowtext\quad \ce This typically results in dividing a larger molecule into s ...

enzymes. In turn, certain β-glucosidases hydrolyze 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 Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...

, also known as the multi-drug resistance 1 transporter ( MDR1). GluCer is implicated in post-Golgi trafficking and drug resistance particularly to

. For instance, a study demonstrated a correlation between cellular

drug resistance Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is ...

and modifications in GluCer

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

. 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

of GluCer synthase is being considered a technique to avoid

insulin resistance Insulin resistance (IR) is a pathological response in which cells in insulin-sensitive tissues in the body fail to respond normally to the hormone insulin or downregulate insulin receptors in response to hyperinsulinemia. Insulin is a horm ...

Ceramide-1-Phosphate

Ceramide-1-phosphate (C1P) is formed by the action of ceramide kinase (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 The enzyme phospholipase A2 (EC 3.1.1.4, PLA2, systematic name phosphatidylcholine 2-acylhydrolase) catalyses the cleavage of fatty acids in position 2 of phospholipids, hydrolyzing the bond between the second fatty acid "tail" and the glycero ...

and is found, along with CK, to be a mediator of

arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega−6 fatty acid 20:4(ω−6), or 20:4(5,8,11,14). It is a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes. Together with omega−3 fatty acids an ...

released in cells in response to a protein called

interleukin Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related ...

-1β (IL-1β) and a lipid-soluble molecule that transports calcium ions (Ca²⁺) across the bilayer, also known as calcium

ionophore In chemistry, an ionophore () is a chemical species that reversibly binds ions. Many ionophores are lipid-soluble entities that transport ions across the cell membrane. Ionophores catalyze ion transport across hydrophobic membranes, such as l ...

. C1P was also previously reported to encourage

cell division Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...

(

mitogenic A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The cell cycle Mitogens ac ...

) in

fibroblasts A fibroblast is a type of biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibrobla ...

, block

by inhibiting acid SMase in

white blood cells White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...

within tissues (

) and increase intracellular free

concentrations in

thyroid The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is a butterfly-shaped gland located in the neck below the Adam's apple. It consists of two connected lobes. The lower two thirds of the lobes are connected by ...

cells. C1P also has known roles in vesicular trafficking, cell survival,

phagocytosis Phagocytosis () is the process by which a cell (biology), cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs ph ...

("cell eating") and

macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

degranulation Degranulation is a cellular process that releases antimicrobial, cytotoxic, or other molecules from secretory vesicles called granules found inside some cells. It is used by several different cells involved in the immune system, including gran ...

Phosphatidylinositol bisphosphate (PIP₂) Lipid Agonist

PIP₂ binds directly to ion channels and modulates their activity. PIP₂ was shown to directly agonizes Inward rectifying potassium channels( K_ir). In this regard intact PIP₂ signals as a bona fide neurotransmitter-like ligand. PIP₂'s interaction with many ion channels suggest that the intact form of PIP₂ has an important signaling role independent of second messenger signaling.

Second messengers from phosphatidylinositol

Phosphatidylinositol bisphosphate (PIP₂) Second Messenger Systems

A general

second messenger system Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form of cell signaling, encompassing both first me ...

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 G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...

for the PIP₂ messenger system produces two effectors,

phospholipase C Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role i ...

(PLC) and

phosphoinositide 3-kinase Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...

(PI3K). PLC as an effector produces two different second messengers,

inositol triphosphate Inositol trisphosphate or inositol 1,4,5-trisphosphate abbreviated InsP3 or Ins3P or IP3 is an inositol phosphate signaling molecule. It is made by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid that is located in the p ...

(IP₃) and

Diacylglycerol A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. Diglycerides are n ...

(DAG). IP₃ is soluble and diffuses freely into the cytoplasm. As a second messenger, it is recognized by the inositol triphosphate receptor (IP3R), a Ca²⁺ channel in the

(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 relaxation. DAG remains bound to the membrane by its

fatty acid In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an ...

"tails" where it recruits and activates both conventional and novel members of the

protein kinase C In cell biology, protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...

family. Thus, both IP₃ and DAG contribute to activation of PKCs.

Phosphoinositide 3-kinase Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...

(PI3K) as an effector phosphorylates phosphatidylinositol bisphosphate (PIP₂) to produce

phosphatidylinositol (3,4,5)-trisphosphate Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases' (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid ...

(PIP₃). PIP₃ has been shown to activate

protein kinase B Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, trans ...

, increase binding to extracellular proteins and ultimately enhance cell survival.

Activators of G-protein coupled receptors

See main article on

Lysophosphatidic acid (LPA)

LPA is the result of

action on

phosphatidic acid Phosphatidic acids are anionic phospholipids important to cell signaling and direct activation of lipid-gated ion channels. Hydrolysis of phosphatidic acid gives rise to one molecule each of glycerol and phosphoric acid and two molecules of fatty a ...

. The SN-1 position can contain either an

ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...

bond or an

ether In organic chemistry, ethers are a class of compounds that contain an ether group, a single oxygen atom bonded to two separate carbon atoms, each part of an organyl group (e.g., alkyl or aryl). They have the general formula , where R and R� ...

bond, with

LPA being found at elevated levels in certain cancers. LPA binds the high-affinity

LPA1, LPA2, and LPA3 (also known as EDG2, EDG4, and EDG7, respectively).

Sphingosine-1-phosphate (S1P)

S1P is present at high concentrations in plasma and secreted locally at elevated concentrations at sites of inflammation. It is formed by the regulated

. It acts through five dedicated high-affinity

G-protein coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large protein family, group of evoluti ...

s, S1P1 - S1P5. 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.

Platelet activating factor (PAF)

PAF is a potent activator of platelet aggregation, inflammation, and anaphylaxis. It is similar to the ubiquitous membrane

phospholipid Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...

except that it contains an

acetyl In organic chemistry, an acetyl group is a functional group denoted by the chemical formula and the structure . It is sometimes represented by the symbol Ac (not to be confused with the element actinium). In IUPAC nomenclature, an acetyl grou ...

-group in the SN-2 position and the SN-1 position contains an

-linkage. PAF signals through a dedicated

, PAFR and is inactivated by PAF acetylhydrolase.

Endocannabinoids

The endogenous

cannabinoids Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoa ...

, or

endocannabinoids Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...

, are endogenous lipids that activate cannabinoid receptors. The first such lipid to be isolated was

anandamide Anandamide (ANA), also referred to as ''N''-arachidonoylethanolamine (AEA) is a fatty acid neurotransmitter belonging to the fatty acid derivative group known as N-acylethanolamine (NAE). Anandamide takes its name from the Sanskrit word ''ananda ...

which is the arachidonoyl

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a chemical compound, compound with the general formula , where R, R', and R″ represent any group, typically organyl functional group, groups or hydrogen at ...

ethanolamine Ethanolamine (2-aminoethanol, monoethanolamine, ETA, or MEA) is a naturally occurring organic chemical compound with the formula or . The molecule is bifunctional, containing both a primary amine and a primary alcohol. Ethanolamine is a colorl ...

. Anandamide is formed via enzymatic release from N-arachidonoyl

phosphatidylethanolamine Phosphatidylethanolamine (PE) is a class of phospholipids found in biological membranes. They are synthesized by the addition of cytidine diphosphate-ethanolamine to diglycerides, releasing cytidine monophosphate. S-Adenosyl methionine, ''S''-Ade ...

by the N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD). Anandamide activates both the CB1 receptor, found primarily in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

, and the CB2 receptor which is found primarily in

lymphocytes A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), and ...

and the periphery. It is found at very low levels (nM) in most tissues and is inactivated by the

fatty acid amide hydrolase Fatty-acid amide hydrolase 1 (FAAH) is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide (AEA), an ''N''-acylethanolamine (NAE) in 1993. In humans, it is encoded by the gene ''FAAH''.; Function ...

. Subsequently, another endocannabinoid was isolated,

2-arachidonoylglycerol 2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous agonist of the CB1 receptor and the primary endogenous ligand for the CB2 receptor. It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is pres ...

, which is produced when

releases

which is then converted to 2-AG by diacylglycerol lipase. 2-AG can also activate both cannabinoid receptors and is inactivated by

monoacylglycerol lipase Monoacylglycerol lipase (EC 3.1.1.23; systematic name glycerol-ester acylhydrolase, also known as MAG lipase, acylglycerol lipase, MAGL, MGL or MGLL) is an enzyme that, in humans, is encoded by the ''MGLL'' gene. MAGL is a 33-kDa, membrane-associ ...

. It is present at approximately 100-times the concentration of

in most tissues. Elevations in either of these lipids causes

analgesia Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professionals ...

and anti-

and tissue protection during states of ischemia, but the precise roles played by these various endocannabinoids are still not totally known and intensive research into their function, metabolism, and regulation is ongoing. One saturated lipid from this class, often called an endocannabinoid, but with no relevant affinity for the CB1 and CB 2 receptor is

palmitoylethanolamide Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, and lipid modulator. A main target of PEA is proposed to be the peroxisome proliferator-activated receptor alpha (PPAR-α). PEA also has affinity to cannabinoid-like G-coupled recept ...

. This signaling lipid has great affinity for the GRP55 receptor and the PPAR alpha receptor. It has been identified as an anti-inflammatory compound already in 1957, and as an analgesic compound in 1975.

Rita Levi-Montalcini Rita Levi-Montalcini ( , ; 22 April 1909 – 30 December 2012) was an Italian neurobiologist. She was awarded the 1986 Nobel Prize in Physiology or Medicine jointly with colleague Stanley Cohen for the discovery of nerve growth factor ( ...

first identified one of its biological mechanisms of action, the inhibition of activated mast cells. Palmitoylethanolamide is the only endocannabinoid available on the market for treatment, as a food supplement.

Prostaglandins

Prostaglandin Prostaglandins (PG) are a group of physiology, physiologically active lipid compounds called eicosanoids that have diverse hormone-like effects in animals. Prostaglandins have been found in almost every Tissue (biology), tissue in humans and ot ...

s are formed through

oxidation Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...

cyclooxygenase Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, ) that is responsible for biosynthesis of prostanoids, including thromboxane and prostaglandins such a ...

s and other prostaglandin synthases. There are currently nine known

( eicosanoid receptors) that largely mediate prostaglandin physiology (although some prostaglandins activate

nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These intracellular receptors work with other proteins to regulate the ex ...

s, see below).

FAHFA

FAHFAs (fatty acid esters of hydroxy fatty acids) are formed in adipose tissue, improve glucose tolerance and also reduce adipose tissue inflammation. Palmitic acid esters of hydroxy-stearic acids (PAHSAs) are among the most bioactive members able to activate

120. Docosahexaenoic acid ester of hydroxy-linoleic acid (DHAHLA) exert anti-inflammatory and pro-resolving properties.

Retinol derivatives

Retinaldehyde Retinal (also known as retinaldehyde) is a polyene chromophore. Retinal, bound to proteins called opsins, is the chemical basis of visual phototransduction, the light-detection stage of visual perception (vision). Some microorganisms use retin ...

is a

retinol Retinol, also called vitamin A1, is a fat-soluble vitamin in the vitamin A family that is found in food and used as a dietary supplement. Retinol or other forms of vitamin A are needed for vision, cellular development, maintenance of skin and ...

(

vitamin A Vitamin A is a fat-soluble vitamin that is an essential nutrient. The term "vitamin A" encompasses a group of chemically related organic compounds that includes retinol, retinyl esters, and several provitamin (precursor) carotenoids, most not ...

) derivative responsible for vision. It binds

rhodopsin Rhodopsin, also known as visual purple, is a protein encoded by the ''RHO'' gene and a G-protein-coupled receptor (GPCR). It is a light-sensitive receptor protein that triggers visual phototransduction in rod cells. Rhodopsin mediates dim ...

, a well-characterized

GPCR G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...

that binds all-cis

retinal Retinal (also known as retinaldehyde) is a polyene chromophore. Retinal, bound to proteins called opsins, is the chemical basis of visual phototransduction, the light-detection stage of visual perception (vision). Some microorganisms use ret ...

in its inactive state. Upon photoisomerization by a

photon A photon () is an elementary particle that is a quantum of the electromagnetic field, including electromagnetic radiation such as light and radio waves, and the force carrier for the electromagnetic force. Photons are massless particles that can ...

the cis-retinal is converted to trans-retinal causing activation of

which ultimately leads to

depolarization In biology, depolarization or hypopolarization is a change within a cell (biology), cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolar ...

of the

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

thereby enabling

visual perception Visual perception is the ability to detect light and use it to form an image of the surrounding Biophysical environment, environment. Photodetection without image formation is classified as ''light sensing''. In most vertebrates, visual percept ...

Activators of nuclear receptors

See the main article on

Steroid Hormones

This large and diverse class of

steroids A steroid is an organic compound with four fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter mem ...

are biosynthesized from

isoprenoids The terpenoids, also known as isoprenoids, are a class of naturally occurring organic chemicals derived from the 5-carbon compound isoprene and its derivatives called terpenes, diterpenes, etc. While sometimes used interchangeably with "terpenes" ...

and structurally resemble

cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...

. Mammalian steroid hormones can be grouped into five groups by the receptors to which they bind:

mineralocorticoids Mineralocorticoids are a class of corticosteroids, which in turn are a class of steroid hormones. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances (electrolyte balance and fluid balance). The primary mi ...

androgens An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...

estrogens Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ma ...

, and

progestogens Progestogens, also sometimes written progestins, progestagens or gestagens, are a class of natural or synthetic steroid hormones that bind to and activate the progesterone receptors (PR). Progesterone is the major and most important progestogen ...

Retinoic acid

Retinol Retinol, also called vitamin A1, is a fat-soluble vitamin in the vitamin A family that is found in food and used as a dietary supplement. Retinol or other forms of vitamin A are needed for vision, cellular development, maintenance of skin and ...

(

) can be metabolized to

retinoic acid Retinoic acid (simplified nomenclature for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that is required for embryonic development, male fertility, regulation of bone growth and immune function. All-''trans ...

which activates

nuclear receptors In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroid hormone, steroids, thyroid hormone, thyroid hormones, vitamins, and certain other molecules. These intracellular receptor (biochemistry) ...

such as the RAR to control differentiation and proliferation of many types of cells during development.

Prostaglandins

The majority of

signaling occurs via

s (see above) although certain

s activate nuclear receptors in the PPAR family. (See article eicosanoid receptors for more information).

References

{{DEFAULTSORT:Lipid Signaling Signal transduction

Sphingolipid second messengers

Ceramide

Sphingosine

Sphingosine-1-Phosphate

Glucosylceramide

Ceramide-1-Phosphate

Phosphatidylinositol bisphosphate (PIP2) Lipid Agonist

Second messengers from phosphatidylinositol

Phosphatidylinositol bisphosphate (PIP2) Second Messenger Systems

Activators of G-protein coupled receptors

Lysophosphatidic acid (LPA)

Sphingosine-1-phosphate (S1P)

Platelet activating factor (PAF)

Endocannabinoids

Prostaglandins

FAHFA

Retinol derivatives

Activators of nuclear receptors

Steroid Hormones

Retinoic acid

Prostaglandins

See also

References

Phosphatidylinositol bisphosphate (PIP₂) Lipid Agonist

Phosphatidylinositol bisphosphate (PIP₂) Second Messenger Systems