Lipid signaling 5419130 206497728 2008-04-18T14:44:15Z Roadnottaken 628366 /* Sphingosine-1-phosphate (S1P) */ [[Image:signaling_lipids2.png|right|thumb|375px|Common lipid signaling molecules:<BR>[[lysophosphatidic acid]] (LPA)<BR> [[sphingosine-1-phosphate]] (S1P)<BR>[[platelet activating factor]] (PAF)<BR>[[anandamide]] or arachidonoyl ethanolamine (AEA)]] '''Lipid signaling,''' broadly defined, refers to any biological signaling event involving a [[lipid]] messenger that binds and activates a [[Receptor (biochemistry)|receptor]]. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms (such as the [[monoamine neurotransmitter]]s) 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. ==Activators of G-protein coupled receptors== See main article on [[G-protein coupled receptors]] ===Lysophosphatidic acid (LPA)=== [[lysophosphatidic acid|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]] [[Lysophospholipid receptor|LPA1]], [[Lysophospholipid receptor|LPA2]], and [[Lysophospholipid receptor|LPA3]] (also known as [[Lysophospholipid receptor|EDG2]], [[Lysophospholipid receptor|EDG4]], and [[Lysophospholipid receptor|EDG7]], respectively). ===Sphingosine-1-phosphate (S1P)=== [[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 receptor]]s, [[Lysophospholipid receptor|S1P1]] - [[Lysophospholipid receptor|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 [[Lysophospholipid receptor|S1P3]]-receptor specific mechanism. ===Platelet activating factor (PAF)=== [[platelet activating factor|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 [[diglyceride|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|Eicosanoids}} [[Prostaglandin]]s are formed through [[oxidation]] of [[arachidonic acid]] by [[cyclooxygenase]]s and other [[prostaglandin synthase]]s. 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). ===Retinoic acid derivatives=== {{main|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 receptor|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 [[retinoic acid receptor|RAR]] and [[RXR]] to mediate differentiation and proliferation of many types of cells. ===Prostaglandins=== {{main|Eicosanoids}} The majority of [[prostaglandin]] signaling occurs via [[GPCR]]s (see above) although certain [[prostaglandin]]s activate nuclear receptors in the [[PPAR]] family. (See article [[eicosanoid receptor]]s for more information). ==Second messengers== {{main|second messenger system}} ===Diacylglycerol=== {{main|diglyceride}} The key event of [[diglyceride|diacylglycerol]] (DAG) signaling is the [[hydrolysis]] of [[Phosphatidylinositol (4,5)-bisphosphate]](PIP2) to DAG and [[inositol triphosphate]](IP3) by a [[Phospholipase#Phospholipase C (PLC)|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 Ca<sup>2+</sup> channel in the [[endoplasmic reticulum]](ER) membrane. The ER acts as intracellular Ca<sup>2+</sup> store. The binding of IP3 to IP3R releases the flow of calcium from the ER into the normally Ca<sup>2+</sup>-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#Protein kinase C|Protein kinase C]] family. Thus, both IP3 and DAG contribute to activation of PKCs.<ref name="pmid1318060">{{cite journal |author=Irvine RF |title=Inositol lipids in cell signalling |journal=Curr. Opin. Cell Biol. |volume=4 |issue=2 |pages=212–9 |year=1992 |pmid=1318060 |doi=}}</ref><ref name="pmid7737456">{{cite journal |author=Nishizuka Y |title=Protein kinase C and lipid signaling for sustained cellular responses |url=http://www.fasebj.org/cgi/reprint/9/7/484|format=pdf|journal=FASEB J. |volume=9 |issue=7 |pages=484–96 |year=1995 |pmid=7737456 |doi=}}</ref> Protein kinase C-α is a conventional PKC and requires both DAG and Ca<sup>2+</sup> for activity. One of the targets activated by PKC-α is [[Phospholipase#Phospholipase D (PLD)|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== *[[Signal transduction#Signaling Molecules|List of signaling molecule types]] *[[Lysophospholipid receptor]]s ==References== <references/> {{Cell_signaling}} {{Lipid_signaling}} [[Category:Signal transduction]]