Thrombinisanextracellularproteasethatisinvolvedintheclottingofbloodandinflammationthroughitsactiononplateletsandendothelialcellsinthevasculatureandthatplaysaroleinthrombosisandmyocardialinfarction.TheproteaseactivatedreceptorsPAR1andPAR4arecellulartargetsofthrombinsignalingandmembersoftheG-proteincoupledreceptorgenefamily.BothofthesereceptorsarecleavedintheirN-terminusbythrombin,unmaskingaportionofthereceptorsequencethatactsitselfasatetheredpeptideligandthatactivatesthereceptor.ThetetheredligandthatactivatesPAR1isSFLLRNandthetetheredligandthatactivatesPAR4isGYPGQV.OthermembersofthefamilyincludePAR2whichisactivatedbytrypsinratherthanthrombinandPAR3whichseemstoplayaroleintheactivationofotherPARsbutdoesnotitselftransduceasignaldirectly.AdditionofpeptideagoNISTexogenouslyinsolutioncanalsoactivatePAR1,PAR2andPAR4.PAR1activationmaybeinvolvedinthedilationofarteriesduringinflammationthroughtheactionofthrombinonendothelialcellsandinplateletactivationbythrombinduringclotting.PAR1andPAR2activationcausebronchodilationinairwayandmayprotectagainstasthma.PAR4activationbythrombinactivatesplateletsduringclottingandmicelackingPAR4haveimpairedclottingandplateletsthatdonotrespondtothrombinsignaling.TheactionofthrombinonPAR1andPAR4onplateletsandendothelialcellsmayalsocontributetovascularpermeABIlityandinflammation.ActivatedPARsappeartocoupleprimarilythroughGq-mediatedstimulationofinositolphosphatemetabolismandintracellularcalciumlevelstoactivateplatelets.PAR1andPAR4alsoappeartocoupletomultipleG-proteinsandtransducesignalsthroughmorethanoneG-proteinmediatedpathwayinsomecircumstances.SignalingbyPAR1andPAR4throughGalpha12pathwayscouplestoRhosignalingandchangesincytoskeletalstructureandcellshape.GiactivationdoesnotappearnecessaryforplateletactivationbyPAR1orPAR4,andplateletactivationbythesereceptorsrequiresanADPsignalperhapsactingthroughtheplatelet-associatedpurinergicreceptorP2Y12.Gi-coupledsignalingmayplayaroleinmitogenicPARsignalinginsomesettingsthroughMapkinaseactivation.ActivationofRhobyPAR1caninducecellulartransformationthroughaGalpha12mediatedmechanismandsustainedrho-dependentphosphorylationofthemyosinlightchainbyPAR1contributestocytoskeletalchangesandactivationofplatelets.SincetheactivationofPARsbyproteasecleavageisirreversIBLetheprimarymechanismfordown-regulationofthePARsignalingcascadeappearstobeinternalizationanddegradationofPARreceptors.

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