Orientation of the Calcium Channel β Relative to the α12.2 Subunit Is Critical for Its Regulation of Channel Activity 英文参考文献.docVIP

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Orientation of the Calcium Channel β Relative to the α12.2 Subunit Is Critical for Its Regulation of Channel Activity 英文参考文献.doc

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Orientation of the Calcium Channel β Relative to the α12.2 Subunit Is Critical for Its Regulation of Channel Activity 英文参考文献

OrientationoftheCalciumChannelbRelativetothe a12.2SubunitIsCriticalforItsRegulationofChannel Activity IuliiaVitko.,AleksandrShcheglovitov.,JoelP.Baumgart,ImillaI.Arias-Olgu?′n¤a,JanetMurbartia′n¤b, JuanManuelArias¤c,EdwardPerez-Reyes* DepartmentofPharmacologyandNeuroscienceGraduateProgram,UniversityofVirginia,Charlottesville,Virginia,UnitedStatesofAmerica Abstract Background:TheCavbsubunitsofhighvoltage-activatedCa2+channelscontrolthetraffickingandbiophysicalpropertiesof thea1subunit.TheCavb-a1interactionsitehasbeenmappedbycrystallographicstudies.Nevertheless,howthisinteraction leadstochannel regulationhasnotbeendetermined.Onehypothesisisthat bsregulatechannelgatingby modulating movementsofIS6.Akeyrequirementforthisdirect-couplingmodelisthatthelinkerconnectingIS6tothea-interaction domain(AID)bearigidstructure. Methodology/PrincipalFindings:Thepresentstudyteststhishypothesisbyalteringtheflexibilityandorientationofthis regionina12.2,thentestingforCavbregulationusingwholecellpatchclampelectrophysiology.Flexibilitywasinducedby replacement ofthemiddle sixamino acidsof theIS6-AIDlinkerwith glycine(PG6). This mutationabolished b2a andb3 subunits ability to shift the voltage dependence of activation and inactivation, and the ability of b2a to produce non- inactivatingcurrents.OrientationofCavbwithrespecttoa12.2wasalteredbydeletionof1,2,or3aminoacidsfromtheIS6- AID linker (Bdel1, Bdel2, Bdel3, respectively). Again, the ability of Cavb subunits to regulate these biophysical properties weretotallyabolishedintheBdel1andBdel3mutants.FunctionalregulationbyCavbsubunitswasrescuedintheBdel2 mutant,indicatingthatthispartofthelinkerformsb-sheet.Theorientationofbwithrespecttoawasconfirmedbythe bimolecularfluorescencecomplementationassay. Conclusions/Significance:TheseresultsshowthattheorientationoftheCavbsubunitrelativetothea12.2subunitiscritical, andsuggestsadditionalpointsofcontactbetweenthesesubunitsarerequiredforCavbtoregulatechannelactivity. Citation:VitkoI,Shcheglovito