Nitricoxide(NO)hasanumberofimportantphysiologicalactionsinthecardiovascularsystem.Intheheart,NOplaysroleinkeepingthevesselspatentviavasodilationandpreventionofplateletaggregation.Italsoplaysanimportantroleinregulatingtheforceandrateofcontraction.InvivoNOisreleasedbyshearstressofligandsthatincreaseintracellularCa2+inendothelialcells.TheincreaseintracellularCa2+activatesnitricoxidesynthaseIII(NOSIII)bypromotingthebindingofCa/Calmodulintotheenzyme.NOSIII,whichisresidentintheGolgicomplex,istransportedtogetherwithcaveolin-1tothecaveolaeattheplasmamembraneviavesicles.ShearstresssignalsviaapotassiumchannelandtheCytoskeleton,whichresultsintyrosinephosphorylationofspecificproteins,activationofphosphatidylinositol3-kinase,andsubsequentlyinactivationofAktkinase.AktactivationbyshearstressbutalsobyVEGFactivatesNOSIIIbyserinephosphorylation,whichincreasestheaffinityofNOSIIIforcalmodulin.AfteragoNISTbindingattheplasmamembrane,NOSIII-activatingreceptorstranslocatetocaveolae.VEGFreceptorsignalsviaitstyrosinekinasedomain.FurThermore,agonistreceptorsactivatecalciumchannelsoftheendoplasmicreticulum(ER)viaphospholipaseCandinositol1,4,5-trisphosphate.ThiscalciumfluxinducesbindingofcalmodulintoNOSIII,whereastheNOSIII-caveolin-1interactionisdisrupted.Atthesametime,NOSIIIistranslocatedintothecytosol.Onbindingofcalmodulin,NOSIIIgeneratesNO,isenhancedbytheinteractionwithHsp90.Onceactivated,NOSIIIcatabolizesL-argininetoNO,whichdiffusesoutofthecell.NOstimulatesguanylate(G-)cyclaseandincreasescGMPlevels.cGMPactivatescGMP-dependentproteinkinase(PKG),cGMP-inhibitedphosphodiesterase(PDEIII),andcGMP-stimulatedphosphodiesterase(PDEII).PKGmayreducetheforceandrateofcontraction,possIBLybyphosphorylatingtroponinIorbyphosphorylatingphospholamban.PDEIIIisinhibitedbytheincreasesincGMPbroughtaboutbyNO.ThismayresultinanincreaseincAMPandcAMP-dependentproteinkinase(PKA).PKAinturnactivatesCa2+channels,counteringtheeffectsofPKG.Incontrast,cGMPmaystimulatePDEII,reducecAMPlevelsandPKAactivity,andtherebyreduceCa2+channelactivity.Ach,acetylcholine.CAT-1,cationicaminoacidtransporter.

Contributor:KosiGramatikoff,PhD

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