Alternative Splicing of the N-Terminal Cytosolic and Transmembrane Domains of P2X7 Controls Gating of the Ion Channel by ADP-Ribosylation 英文参考文献.docVIP

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Alternative Splicing of the N-Terminal Cytosolic and Transmembrane Domains of P2X7 Controls Gating of the Ion Channel by ADP-Ribosylation 英文参考文献.doc

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Alternative Splicing of the N-Terminal Cytosolic and Transmembrane Domains of P2X7 Controls Gating of the Ion Channel by ADP-Ribosylation 英文参考文献

AlternativeSplicingoftheN-TerminalCytosolicand TransmembraneDomainsofP2X7ControlsGatingofthe IonChannelbyADP-Ribosylation NicoleSchwarz1,LaurentDrouot2,AnnetteNicke3,RalfFliegert4,OlivierBoyer2,AndreasH.Guse4, FriedrichHaag1,SahilAdriouch2,FriedrichKoch-Nolte1* 1InstituteofImmunology,UniversityMedicalCenterHamburg-Eppendorf,Hamburg,Germany,2Inserm,U905,UniversityofRouen,InstituteforResearchandInnovation in Biomedicine (IRIB), Normandy, France, 3Max Planck Institute for Experimental Medicine, Go¨ttingen, Germany, 4The Calcium Signaling Group, Department of BiochemistryandSignalTransduction,UniversityMedicalCenterHamburg-Eppendorf,Hamburg,Germany Abstract P2X7 is a homotrimeric ion channel with two transmembrane domains and a large extracellular ATP-binding domain. It playsakeyroleintheresponseofimmunecellstodangersignalsreleasedfromcellsatsitesofinflammation.Gatingof murineP2X7canbeinducedbythesolubleligandATP,aswellasbyNAD -dependentADP-ribosylationofarginine125, + aposttranslationalproteinmodificationcatalyzedbythetoxin-relatedecto-enzymesART2.1andART2.2.R125islocatedat theedgeoftheligand-bindingcrevice.Recently,analternativesplicevariantofP2X7,designatedP2X7(k),wasdiscovered that differs from the previously described variant P2X7(a) in the N-terminal 42 amino acid residues composing the first cytosolicdomainandmostoftheTm1domain.HerewecomparethetwosplicevariantsofmurineP2X7withrespectto theirsensitivitiestogatingbyADP-ribosylationintransfectedHEKcells.OurresultsshowthattheP2X7(k)variantissensitive toactivationby ADP-ribosylationwhereas theP2X7(a)variantis insensitive, despitehighercell surfaceexpressionlevels. Interestingly, a single point mutation (R276K) renders the P2X7(a) variant sensitive to activation by ADP-ribosylation. Residue276islocatedattheinterfaceofneighboringsubunitsapproximatelyhalfwaybetweentheADP-ribosylationsite and the transmembrane domains. Moreover, we show that naive and regulatory T cells preferentially express the more sensitiv