title: Proteinase-activated receptor-2 stimulates prostaglandin production in keratinocytes: analysis of prostaglandin receptors on human melanocytes and effects of PGE2 and PGF2alpha on melanocyte dendricity.
abstract: Prostaglandins (PG) are key mediators of diverse functions in the skin and several reports suggest that PG mediate post-inflammatory pigmentary changes through modulation of melanocyte dendricity and melanin synthesis. The proteinase-activated receptor 2 (PAR-2) is important for skin pigmentation because activation of keratinocyte PAR-2 stimulates uptake of melanosomes through phagocytosis in a Rho-dependent manner. In this report, we show that activation of keratinocyte PAR-2 stimulates release of PGE(2) and PGF(2alpha) and that PGE(2) and PGF(2alpha) act as paracrine factors that stimulate melanocyte dendricity. We characterized the expression of the EP and FP receptors in human melanocytes and show that human melanocytes express EP1 and EP3, and the FP receptor, but not EP2 and EP4. Treatment of melanocytes with EP1 and EP3 receptor agonists resulted in increased melanocyte dendricity, indicating that both EP1 and EP3 receptor signaling contribute to PGE(2)-mediated melanocyte dendricity. Certain EP3 receptor subtypes have been shown to increase adenosine 3',5'-cyclic monophosphate (cAMP) through coupling to Gs, whereas EP1 is known to couple to Gq to activate phospholipase C with elevation in Ca(2+). The cAMP/protein kinase A system is known to modulate melanocyte dendrite formation through modulation of Rac and Rho activity. Neither PGF(2alpha) or PGE(2) elevated cAMP in human melanocytes showing that dendricity observed in response to PGE(2) and PGF(2alpha) is cAMP-independent. Our data suggest that PAR-2 mediates cutaneous pigmentation both through increased uptake of melanosomes by keratinocytes, as well as by release of PGE(2) and PGF(2alpha) that stimulate melanocyte dendricity through EP1, EP3, and FP receptors.
authors.affiliation: Department of Dermatology, School of Medicine, University of Rochester, Rochester, New York, USA. Glynis_Scott@urmc.rochester.edu
authors.forename: Glynis
authors.initials: G
authors.lastname: Scott
authors.forename: Sonya
authors.initials: S
authors.lastname: Leopardi
authors.forename: Stacey
authors.initials: S
authors.lastname: Printup
authors.forename: Namrita
authors.initials: N
authors.lastname: Malhi
authors.forename: Miri
authors.initials: M
authors.lastname: Seiberg
authors.forename: Randi
authors.initials: R
authors.lastname: Lapoint
mesh_terms: D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D015237:Dinoprost / Q000378:metabolism* / Q000494:pharmacology; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016595:Misoprostol / Q000494:pharmacology; D010120:Oxytocics / Q000494:pharmacology; D019899:Paracrine Communication / Q000502:physiology; D044464:Receptor, PAR-2 / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype
chemical_list: C092396:17-phenyltrinorprostaglandin E2; D010120:Oxytocics; C545635:PTGER1 protein, human; C545644:PTGER2 protein, human; C545647:PTGER3 protein, human; C545650:PTGER4 protein, human; D044464:Receptor, PAR-2; D011982:Receptors, Prostaglandin; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; C034671:prostaglandin F2alpha receptor; D016595:Misoprostol; D015237:Dinoprost; D000242:Cyclic AMP; D015232:Dinoprostone