Prostaglandin 92336 224417604 2008-07-08T19:30:20Z 24.150.41.133 /* Function */ [[Image:Prostaglandin E1.svg|thumb|right|[[Alprostadil|E<sub>1</sub> - Alprostadil]]]] [[Image:Prostacyclin-2D-skeletal.png|thumb|[[Prostacyclin|I<sub>2</sub> - Prostacyclin]]]] A '''prostaglandin''' is any member of a group of [[lipid]] compounds that are derived enzymatically from [[fatty acid]]s and have important functions in the [[animal]] body. Every prostaglandin contains 20 [[carbon]] atoms, including a 5-carbon ring. They are mediators and have a variety of strong [[physiology|physiological]] effects; although they are technically [[hormone]]s, they are rarely classified as such. The prostaglandins together with the [[thromboxane]]s and [[prostacyclin]]s form the [[prostanoid]] class of fatty acid derivatives; the prostanoid class is a subclass of [[eicosanoid]]s. == History and name == <!-- Deleted image removed: [[Image:Ulf-von-Euler.gif|left|frame|Ulf von Euler, a Nobel laureate, discovered and named prostaglandin {{puic|Image:Image_name.ext|log=2008 April 2}}]] --> The name ''prostaglandin'' derives from the [[prostate gland]]. When prostaglandin was first isolated from [[seminal fluid]] in [[1935]] by the Swedish [[physiology|physiologist]] [[Ulf von Euler]],<ref>Von Euler US. Über die spezifische blutdrucksenkende Substanz des menschlichen Prostata- und Samenblasensekrets. Klin Wochenschr 1935;14:1182–1183.</ref> and independently by M.W. Goldblatt,<ref>Goldblatt MW. Properties of human seminal plasma. ''J Physiol'' 1935;84:208-18. PMID 16994667.</ref> it was believed to be part of the prostatic secretions (in actuality prostaglandins are produced by the [[seminal vesicles]]); it was later shown that many other tissues secrete prostaglandins for various functions. In [[1971]], it was determined that [[aspirin]]-like drugs could inhibit the synthesis of prostaglandins. The [[biochemist]]s [[Sune K. Bergström]], [[Bengt I. Samuelsson]] and [[John R. Vane]] jointly received the [[1982]] [[Nobel Prize in Physiology or Medicine]] for their research on prostaglandins. == Biochemistry == === Biosynthesis === [[Image:Eicosanoid synthesis.svg|thumb|300px|Biosynthesis of eicosanoids. (series-2)]]Prostaglandins are found in virtually all tissues and organs. These are [[autocrine]] and [[paracrine]] lipid mediators that act upon [[platelet]], [[endothelium]], [[uterus|uterine]] and [[mast cell]]s, among others. They are synthesized in the cell from the [[essential fatty acid]]s<ref name="merck">Dorlands Medical Dictionary [http://www.mercksource.com/pp/us/cns/cns_hl_dorlands.jspzQzpgzEzzSzppdocszSzuszSzcommonzSzdorlandszSzdorlandzSzdmd_p_36zPzhtm#1085994] URL reference on 10/23/05.</ref> (EFAs). An intermediate is created by [[phospholipase A2|phospholipase-A<sub>2</sub>]], then passed into one of either the [[Cyclooxygenase|cyclooxygenase pathway]] or the [[Lipoxygenase|lipoxygenase pathway]] to form either prostaglandin and thromboxane or [[leukotriene]]. The cyclooxygenase pathway produces [[thromboxane]], [[prostacyclin]] and prostaglandin D, E and F. The lipoxygenase pathway is active in [[leukocyte]]s and in [[macrophage]]s and synthesizes leukotrienes. {| class="wikitable" | '''Name''' || '''EFA Type''' || '''Series''' |- | [[Gamma-linolenic acid]] (GLA) ''via'' [[Dihomo-gamma-linolenic acid|DGLA]] || [[omega-6 fatty acid|ω-6]] || series-1 |- | [[Arachidonic acid]] (AA) || ω-6 || series-2 |- | [[Eicosapentaenoic acid]] (EPA) || [[omega-3 fatty acid|ω-3]] || series-3 |} === Release of prostaglandins from the cell === Prostaglandins were originally believed to leave the cells via passive diffusion because of their high lipophilicity. The discovery of the [[prostaglandin transporter]] (PGT, SLCO2A1), which mediates the cellular uptake of prostaglandin, demonstrated that diffusion cannot explain the penetration of prostaglandin through the cellular membrane. The release of prostaglandin has now also been shown to be mediated by a specific transporter, namely the [[multidrug resistance protein 4]] (MRP4, ABCC4), a member of the [[ATP-binding cassette transporter]] superfamily. Whether MRP4 is the only transporter releasing prostaglandins from the cells is still unclear. ==== Cyclooxygenases ==== Prostaglandins are produced following the sequential oxidation of AA, DGLA or EPA by [[cyclooxygenase]]s (COX-1 and COX-2) and terminal prostaglandin synthases. The classic dogma is as follows: * COX-1 is responsible for the baseline levels of prostaglandins. * COX-2 produces prostaglandins through stimulation. However, while COX-1 and COX-2 are both located in the [[blood vessels]], [[stomach]] and the [[kidneys]], prostaglandin levels are increased by COX-2 in scenarios of [[inflammation]]. A third form of COX, termed COX-3, has been identified, but its exact function is still being determined. ==== Prostaglandin E synthase ==== Prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) is generated from the action of [[prostaglandin E synthase]]s on prostaglandin H<sub>2</sub> (PGH<sub>2</sub>). Several prostaglandin E synthases have been identified. To date, microsomal prostaglandin E synthase-1 emerges as a key enzyme in the formation of PGE<sub>2</sub>. ==== Other terminal prostaglandin synthases ==== Terminal prostaglandin synthases have been identified that are responsible for the formation of other prostaglandins. For example, hematopoietic and [[lipocalin]] [[prostaglandin D synthase]]s (hPGDS and lPGDS) are responsible for the formation of PGD<sub>2</sub> from PGH<sub>2</sub>. Similarly, prostacyclin (PGI<sub>2</sub>) synthase (PGIS) converts PGH<sub>2</sub> into PGI<sub>2</sub>. A thromboxane synthase ([[thromboxane-A synthase|TxAS]]) has also been idenfitied. [[Prostaglandin F synthase]] (PGFS) catalyzes the formation of 9α,11β-PGF<sub>2α,β</sub> from PGD<sub>2</sub> and PGF<sub>2α</sub> from PGH<sub>2</sub> in the presence of NADPH. This enzyme has recently been crystallyzed in complex with PGD<sub>2</sub><ref>{{cite journal |author=Komoto J, Yamada T, Watanabe K, Takusagawa F |title=Crystal structure of human prostaglandin F synthase (AKR1C3) |journal=Biochemistry |volume=43 |issue=8 |pages=2188–98 |year=2004 |pmid=14979715 |doi=10.1021/bi036046x}}</ref> and bimatoprost<ref>{{cite journal |author=Komoto J, Yamada T, Watanabe K, Woodward D, Takusagawa F |title=Prostaglandin F2alpha formation from prostaglandin H2 by prostaglandin F synthase (PGFS): crystal structure of PGFS containing bimatoprost |journal=Biochemistry |volume=45 |issue=7 |pages=1987–96 |year=2006 |pmid=16475787 |doi=10.1021/bi051861t}}</ref> (a synthetic analogue of PGF<sub>2α</sub>). == Function == There are currently nine known [[prostaglandin receptor]]s on various cell types. Prostaglandins ligate a subfamily of cell surface seven-transmembrane receptors, [[G-protein-coupled receptor]]s. These receptors are termed DP1-2, EP1-4, FP, IP, and TP, corresponding to the receptor that ligates the corresponding prostaglandin (e.g., DP1-2 receptors bind to [[PGD2]]). These varied receptors mean that Prostaglandins thus act on a variety of cells, and have a wide variety of actions: * cause constriction or dilatation in [[smooth muscle|vascular smooth muscle]] cells * cause aggregation or disaggregation of [[platelet]]s * sensitize spinal [[neuron]]s to pain * decrease intraocular pressure * regulate inflammatory mediation * regulate [[calcium]] movement * control [[hormone]] regulation * control [[cell growth]] Prostaglandins are potent but have a short half-life before being inactivated and excreted. Therefore, they exert only a [[paracrine]] (locally active) or [[autocrine]] (acting on the same cell from which it is synthesized) function. ==Types== <!--PGF2alpha redirects here--> Following is a comparision of the prostaglandin types [[Prostaglandin I2|Prostaglandin I<sub>2</sub>]] (PGI<sub>2</sub>), [[Dinoprostone|Prostaglandin E<sub>2</sub>]] (PGE<sub>2</sub>) and [[PGF2alpha|Prostaglandin F<sub>2α</sub>]] (PGF<sub>2α</sub>). {| class="wikitable" |- ! Type ! [[Prostaglandin receptor|Receptor]] ! Function |- | '''[[Prostaglandin I2|PGI<sub>2</sub>]]''' | IP | *[[vasodilatation]] *inhibit [[platelet aggregation]] * [[bronchodilatation]] |- | rowspan=4 | '''[[Dinoprostone|PGE<sub>2</sub>]]''' | EP<sub>1</sub> | * [[bronchoconstriction]] * [[GI tract]] [[smooth muscle]] contraction |- | EP<sub>2</sub> | * [[bronchodilatation]] * [[GI tract]] [[smooth muscle]] relaxation * [[vasodilatation]] |- | EP<sub>3</sub> | * &darr; [[stomach|gastric]] acid secretion * &uarr; [[stomach|gastric]] [[mucus]] secretion * [[uterus]] contraction (when pregnant) * [[GI tract]] [[smooth muscle]] contraction * [[lipolysis]] inhibition * &uarr; [[autonomous ns|autonomic]] [[neurotransmitters]] <ref name=Rang> Pharmacology, (Rang, Dale, Ritter & Moore, ISBN 0443071454, 5:th ed., Churchill Livingstone 2003) Page 234 </ref> |- | Unspecified | * [[hyperalgesia]]<ref name=Rang/> * [[Fever|pyrogenic]] |- | '''[[PGF2alpha|PGF<sub>2α</sub>]]''' | FP | * [[uterus]] contraction * [[bronchoconstriction]] |} == Role in pharmacology == ===Inhibition=== {{see also|Prostaglandin antagonist|Mechanism of action of aspirin}} Examples of prostaglandin antagonists are: *[[NSAID]]s (inhibit cyclooxygenase) *[[Corticosteroids]] (inhibit phospholipase A2 production) * [[COX-2 selective inhibitors]] or coxibs However, both NSAIDs and Coxibs can raise the risk of [[myocardial infarction]]. ===Clinical uses=== Synthetic prostaglandins are used: * To induce [[childbirth]] (parturition) or [[abortion]] (PGE<sub>2</sub> or PGF<sub>2</sub>, with or without [[mifepristone]], a progesterone antagonist); * To prevent closure of [[patent ductus arteriosus]] in newborns with particular [[cyanotic heart defect]]s (PGE<sub>1</sub>) * To prevent and treat [[peptic ulcer]]s (PGE) * As a [[vasodilation|vasodilator]] in severe [[Raynaud's phenomenon]] or [[ischemia]] of a limb * In [[pulmonary hypertension]] * In treatment of [[glaucoma]] (as in [[bimatoprost]] ophthalmic solution, a synthetic prostamide analog with ocular hypotensive activity) * To treat [[erectile dysfunction]] or in penile rehabilitation following surgery (PGE1 as [[alprostadil]]).<ref name="muse">Medscape ''Early Penile Rehabilitation Helps Reduce Later Intractable ED'' [http://www.medscape.com/viewarticle/515218] URL reference on 10/23/05.</ref> * To treat [[egg bound|egg binding]] in small [[birds]]<ref>{{cite web |url=http://www.michvma.org/documents/MVC%20Proceedings/Labonde2.pdf |title=Avian Reproductive and Pediatric Disorders |accessdate=2008-01-26 |last=LaBonde, MS, DVM |first=Jerry| publisher=Michigan Veterinary Medical Association}}</ref> == References == {{Reflist|2}} ==External links== * {{MeshName|Prostaglandins}} {{hormones}} {{Eicosanoids}} {{Prostaglandins}} [[Category:Prostaglandins]] [[de:Prostaglandin]] [[es:Prostaglandina]] [[fr:Prostaglandine]] [[it:Prostaglandine]] [[he:פרוסטגלנדין]] [[lt:Prostaglandinai]] [[nl:Prostaglandinen]] [[ja:プロスタグランジン]] [[no:Prostaglandin]] [[nn:Prostaglandin]] [[pl:Prostaglandyny]] [[pt:Prostaglandina]] [[ru:Простагландины]] [[sl:Prostaglandin]] [[fi:Prostaglandiini]] [[sv:Prostaglandin]] [[tr:Prostaglandin]] [[uk:Простагландини]] [[vi:Prostaglandin]] [[zh:前列腺素]]