Activation of cGMP-Dependent Protein Kinase Stimulates Cardiac ATP-Sensitive Potassium Channels via a ROSCalmodulinCaMKII Signaling Cascade 英文参考文献.docVIP

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Activation of cGMP-Dependent Protein Kinase Stimulates Cardiac ATP-Sensitive Potassium Channels via a ROSCalmodulinCaMKII Signaling Cascade 英文参考文献.doc

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Activation of cGMP-Dependent Protein Kinase Stimulates Cardiac ATP-Sensitive Potassium Channels via a ROSCalmodulinCaMKII Signaling Cascade 英文参考文献

ActivationofcGMP-DependentProteinKinase StimulatesCardiacATP-SensitivePotassiumChannelsvia aROS/Calmodulin/CaMKIISignalingCascade YongpingChai1,Dai-MinZhang1,Yu-FungLin1,2* 1DepartmentsofPhysiologyandMembraneBiology,UniversityofCaliforniaDavis,Davis,California,UnitedStatesofAmerica,2DepartmentofAnesthesiology,University ofCaliforniaDavis,Davis,California,UnitedStatesofAmerica Abstract Background: Cyclic GMP (cGMP)-dependent protein kinase (PKG) is recognized as an important signaling component in diversecelltypes.PKGmayinfluencethefunctionofcardiacATP-sensitivepotassium(KATP)channels,anionchannelcritical forstressadaptationintheheart;however,theunderlyingmechanismremainslargelyunknown.Thepresentstudywas designedtoaddressthisissue. Methods and Findings: Single-channel recordings of cardiac KATP channels were performed in both cell-attached and inside-out patch configurations using transfected human embryonic kidney (HEK)293 cells and rabbit ventricular cardiomyocytes. We found that Kir6.2/SUR2A (the cardiac-type KATP) channels were activated by cGMP-selective phosphodiesterase inhibitor zaprinast in a concentration-dependent manner in cell-attached patches obtained from HEK293cells,aneffectmimickedbythemembrane-permeablecGMPanalog8-bromo-cGMPwhereasabolishedbyselective PKG inhibitors. Intriguingly, direct application of PKG moderately reduced rather than augmented Kir6.2/SUR2A single- channel currents in excised, inside-out patches. Moreover, PKG stimulation of Kir6.2/SUR2A channels in intact cells was abrogated by ROS/H2O2 scavenging, antagonism of calmodulin, and blockade of calcium/calmodulin-dependent protein kinaseII(CaMKII),respectively.ExogenousH2O2alsoconcentration-dependentlystimulatedKir6.2/SUR2Achannelsinintact cells,anditseffectwaspreventedbyinhibitionofcalmodulinorCaMKII.PKGstimulationofKATPchannelswasconfirmedin intact ventricular cardiomyocytes, which was ROS- and CaMKII-dependent. Kinetically, PKG appeared to stimulate these channelsbydestabilizin