Ankyrin-B Coordinates the NaK ATPase, NaCa Exchanger, and InsP3 Receptor in a Cardiac T-TubuleSR Microdomain.docVIP

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Ankyrin-B Coordinates the NaK ATPase, NaCa Exchanger, and InsP3 Receptor in a Cardiac T-TubuleSR Microdomain.doc

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Ankyrin-B Coordinates the NaK ATPase, NaCa Exchanger, and InsP3 Receptor in a Cardiac T-TubuleSR Microdomain

o Openaccess,freelyavailableonline PL S BIOLOGY Ankyrin-BCoordinatestheNa/KATPase, Na/CaExchanger,andInsP3Receptor inaCardiacT-Tubule/SRMicrodomain Peter J.Mohler1*,Jonathan Q.Davis2,Vann Bennett2* 1Department ofPathology, VanderbiltUniversity,Nashville, Tennessee, UnitedStates ofAmerica, 2Howard HughesMedicalInstitute andDepartments ofCellBiology, Biochemistry,andNeurosciences,DukeUniversityMedicalCenter,Durham,NorthCarolina,UnitedStatesofAmerica We report identification of an ankyrin-B-based macromolecular complex of Na/K ATPase (alpha 1 and alpha 2 isoforms),Na/Caexchanger1,andInsP3receptorthatislocalizedincardiomyocyteT-tubulesindiscretemicrodomains distinct from classic dihydropyridine receptor/ryanodine receptor ‘‘dyads.’’ E1425G mutation of ankyrin-B, which causes human cardiac arrhythmia, also blocks binding of ankyrin-B to all three components of the complex. The ankyrin-B complex is markedly reduced in adult ankyrin-Bt/à cardiomyocytes, which may explain elevated [Ca2t]i transients in these cells. Thus, loss of the ankyrin-B complex provides a molecular basis for cardiac arrhythmia in humans and mice. T-tubule-associated ankyrin-B, Na/Ca exchanger, and Na/K ATPase are not present in skeletal muscle,whereankyrin-Bisexpressedat10-foldlowerlevelsthaninheart.Ankyrin-Balsoisnotabundantlyexpressed insmoothmuscle.Weproposethattheankyrin-B-basedcomplexisaspecializedadaptationofcardiomyocyteswitha roleforcytosolicCa2t modulation. Citation:MohlerPJ,DavisJQ,BennettV(2005)Ankyrin-BcoordinatestheNa/KATPase,Na/Caexchanger,andInsP3receptorinacardiacT-tubule/SRmicrodomain.PLoSBiol 3(12):e423. NCX1, NKA, and intracellular Ca2t stores is described in smooth muscle [14], the relative localizations of these Introduction DefectsinCa2thomeostasisunderliemajordiseasesofthe heartincludingcongestiveheartfailure,cardiachypertrophy, and fatal cardiac arrhythmias [1,2]. Ca2t ions enter cardio- myocytes through voltage-sensitive Ca2t channels (dihydro- pyridine receptor [DH