RhoA GTPase Switch Controls Cx43-Hemichannel Activity through the Contractile System 英文参考文献.docVIP

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RhoA GTPase Switch Controls Cx43-Hemichannel Activity through the Contractile System 英文参考文献.doc

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RhoA GTPase Switch Controls Cx43-Hemichannel Activity through the Contractile System 英文参考文献

RhoAGTPaseSwitchControlsCx43-HemichannelActivity throughtheContractileSystem RafPonsaerts1*.,CatheleyneD’hondt1.,Fre′dericHertens1,JanB.Parys1,LucLeybaert2, JohanVereecke1,BernardHimpens1,GeertBultynck1* 1LaboratoryofMolecularandCellularSignaling,DepartmentofCellularandMolecularMedicine,CampusGasthuisbergO/N-1,FacultyofMedicine,KULeuven,Leuven, Belgium,2DepartmentofBasicMedicalSciences,PhysiologyGroup,FacultyofMedicineandHealthSciences,GhentUniversity,Ghent,Belgium Abstract ATP-dependentparacrinesignaling,mediatedviathereleaseofATPthroughplasmamembrane-embeddedhemichannels oftheconnexinfamily,coordinatesasynchronizedresponsebetweenneighboringcells.Connexin43(Cx43)hemichannels that are present in the plasma membrane need to be tightly regulated to ensure cell viability. In monolayers of bovine corneal endothelial cells (BCEC),Cx43-mediated ATP release is strongly inhibited when the cells are treated with inflammatory mediators, in particular thrombin and histamine. In this study we investigated the involvement of RhoA activationintheinhibitionofhemichannel-mediatedATPreleaseinBCEC.WefoundthatRhoAactivationoccursrapidlyand transientlyuponthrombintreatmentofBCEC.TheRhoAactivitycorrelatedwiththeonsetofactomyosincontractilitythatis involved intheinhibition ofCx43hemichannels. RhoAactivation andinhibitionof Cx43-hemichannelactivitywereboth prevented by pre-treatment of the cells with C3-toxin as well as knock down of RhoA by siRNA. These findings provide evidence that RhoA activation is a key player in thrombin-induced inhibition of Cx43-hemichannel activity. This study demonstratesthatRhoAGTPaseactivityisinvolvedintheacuteinhibitionofATP-dependentparacrinesignaling,mediated byCx43hemichannels,inresponsetotheinflammatorymediatorthrombin.Therefore,RhoAappearstobeanimportant molecular switch that controls Cx43 hemichannel openings and hemichannel-mediated ATP-dependent paracrine intercellularcommunicationunder(patho)physiologicalconditionsofstress. Citation:PonsaertsR