Purinergic Activation of Ca2+-Permeable TRPV4 Channels Is Essential for Mechano-Sensitivity in the Aldosterone-Sensitive Distal Nephron 英文参考文献.docVIP

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Purinergic Activation of Ca2+-Permeable TRPV4 Channels Is Essential for Mechano-Sensitivity in the Aldosterone-Sensitive Distal Nephron 英文参考文献.doc

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PurinergicActivationofCa2-PermeableTRPV4ChannelsIsEssentialforMechano-SensitivityintheAldosterone-SensitiveDistalNephron英文参考文献

PurinergicActivationofCa2+-PermeableTRPV4Channels IsEssentialforMechano-Sensitivityinthe Aldosterone-SensitiveDistalNephron MykolaMamenko,OlegZaika,MinJin,RogerG.O’Neil,OlehPochynyuk* DepartmentofIntegrativeBiologyandPharmacology,TheUniversityofTexasHealthScienceCenteratHouston,Houston,Texas,UnitedStatesofAmerica Abstract Mechanical forces are known to induce increases of [Ca2+]i in the aldosterone-sensitive distal nephron (ASDN) cells to regulateepithelialtransport.Atthesametime,mechanicalstressstimulatesATPreleasefromASDNcells.Inthisstudy,we 2+ combined ratiometricFura-2basedmonitoringof[Ca ]i infreshlyisolated split-openedASDNwithtargeteddeletionof P2Y2andTRPV4inmicetoprobearoleforpurinergicsignalinginmediatingmechano-sensitiveresponsesinASDNcells. ATPapplicationcausesareproducibletransientCa2+peakfollowedbyasustainedplateau.Individualcellsofthecortical collectingduct(CCD)andtheconnectingtubule(CNT)respondtopurinergicstimulationwithcomparativeelevationsof 2+ 2+ [Ca ]i. Furthermore, ATP-induced Ca -responses are nearly identical in both principal (AQP2-positive) and intercalated (AQP2-negative) cells as was confirmed using immunohistochemistry in split-opened ASDN. UTP application produces 2+ elevationsof[Ca ]isimilartothatobservedwithATPsuggestingadominantroleofP2Y2-likereceptorsingenerationof 2+ 2+ [Ca ]iresponse.Indeed,geneticdeletionofP2Y2receptorsdecreasesthemagnitudeofATP-inducedandUTP-inducedCa 2+ responses by more than 70% and 90%, respectively. Both intracellular and extracellular sources of Ca appeared to contributetothegenerationofATP-inducedCa2+responseinASDNcells.Importantly,flow-andhypotonic-inducedCa elevationsaremarkedlybluntedinP2Y22/2mice.Wefurtherdemonstratedthatactivationofmechano-sensitiveTRPV4 2+ 2+ channelplaysamajorroleinthesustained[Ca ]ielevationduringpurinergicstimulation.Consistentwiththis,ATP-induced 2+ Ca plateauaredramaticallyattenuatedinTRV42/2mice.InhibitionofTRPCchannelswith10mMBTP2alsodecreased 2+ ATP-inducedCa plateau