Activationoftheprotease-activatedGPCRsinplateletscontributestoplateletactivationinclotting.Theprotease-activatedreceptorsPAR1andPAR4arecleavedbytheproteasethrombin,releasingatetheredpeptideligandthatactivatesthereceptorandtriggersintracellularcalciumrelease.PlateletsfrommicelackingthePAR4genearenotactivatedbythrombinandareimpairedinclotting,supportingtheimportanceofthrombinsignalingthroughPAR4inclotting.HumanplateletsexpressbothPAR1andPAR4,withPAR1playingamoredominantroleinclottinginhumans.CalciumreleaseinducedbyPARsactivatesPKC,modulatingintegrinalphaIIBbeta3(glycoproteinIIb/IIIa)andopeningintegrinligandbindingsitestocontributetoplateletaggregation.IntracellularcalciumincreasesinducedbythrombinactivatesphospholipaseA2,liberatingarachidonicacid,thefirststepinprostaglandinandthromboxanebiosynthesis.Ras/MapkinaseactivationbythePARreceptorsalsoactivatesphospholipaseA2.TheactivationofPAR-inducedplateletaggregationisinhibitedbyaspirin,indicatingthatthromboxaneproductioninducedbyPARsignalingcontributestoplateletactivation.ArachidonicacidisconvertedtotheprostaglandinPGG2bytheenzymeCox-1inplatelets,andCox-1isinhibitedbyaspirin,reducingthromboxaneA2productionbyplatelets.Thromboxaneisapotentvasoconstrictorandplateletactivator,soinhibitionofCox-1inplateletsbyaspirinmayexplainsomeofthecardioprotectiveactionsofaspirin.

Contributor:KosiGramatikoff,PhD

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