Lipid signaling

  Lipid signaling, broadly defined, refers to any biological signaling event involving a lipid messenger that binds and activates a receptor. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms (such as the monoamine neurotransmitters) because lipids can freely diffuse through membranes. 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.

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Activators of G-protein coupled receptors

See main article on G-protein coupled receptors

Lysophosphatidic acid (LPA)

LPA 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).

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 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.

Platelet activating factor (PAF)

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

The Endocannabinoids

The endogenous cannabinoids, 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.

Prostaglandins

Main article: Eicosanoids

Prostaglandins are formed through oxidation of arachidonic acid by cyclooxygenases and other prostaglandin synthases. There are currently nine known G-protein coupled receptors (eicosanoid receptors) that largely mediate prostaglandin physiology (although some prostaglandins activate nuclear receptors, see below).

Retinoic acid derivatives

Main article: visual cycle

Retinaldehyde is a retinoic acid 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 ulitmately leads to depolarization of the neuron thereby enabling visual perception.

Activators of nuclear receptors

See the main article on nuclear receptors

Steroid Hormones

This large and diverse class of steroids are biosynthesized from isoprenoids and structurally resemble cholesterol. Mammalian steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestagens.

Retinoic acid Derivatives

A number of retinol (vitamin A) derivatives activate nuclear receptors such as the RAR and RXR to mediate differentiation and proliferation of many types of cells.

Prostaglandins

Main article: Eicosanoids

The majority of prostaglandin signaling occurs via GPCRs (see above) although certain prostaglandins activate nuclear receptors in the PPAR family. (See article eicosanoid receptors for more information).

Second messengers

Main article: second messenger system

Diacylglycerol

Main article: diglyceride

The key event of diacylglycerol (DAG) signaling is the hydrolysis of Phosphatidylinositol (4,5)-bisphosphate(PIP2) to DAG and inositol triphosphate(IP3) by a phospholipase C (PLC) enzyme. All six known families of PLC catalyze this reaction. IP3 is soluble and diffuses freely into the cytoplasm. It is recognised by the inositol triphosphate receptor(IP3R), a Ca²⁺ channel in the endoplasmic reticulum(ER) membrane. The ER acts as intracellular Ca²⁺ store. The binding of IP3 to IP3R releases the flow of calcium from the ER into the normally Ca²⁺-poor cytoplasm, which then triggers various events of calcium signaling. 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.^[1][2]

Protein kinase C-α is a conventional PKC and requires both DAG and Ca²⁺ for activity. One of the targets activated by PKC-α is phospholipase D, which hydrolyses phosphatidylcholine(PC) to choline and phosphatidic acid. The latter is rapidly converted to DAG. PC-derived DAG can be distinguished from PIP2-derived as their differ in their fatty acid composition. PC forms the bulk of the lipids of the plasma membrane and provides an inexhaustible supply of substrates for PLD. DAG produced through this mechanism may continue to activate PKC hours after the initial extracellular stimulus.

See also

• List of signaling molecule types
• Lysophospholipid receptors

References

1. ^ Irvine RF (1992). "Inositol lipids in cell signalling". Curr. Opin. Cell Biol. 4 (2): 212–9. PMID 1318060.
2. ^ Nishizuka Y (1995). "Protein kinase C and lipid signaling for sustained cellular responses" (pdf). FASEB J. 9 (7): 484–96. PMID 7737456.