receptors(RyR2s)ishypothesizedtocontributetoarrhythmogenesisinAF,butthemolecularmechanisms areincompletelyunderstood.Here,wehaveshownthatmicewithageneticgain-of-functiondefectinRyr2 (whichwetermedRyr2 R176Q/+ mice)didnotexhibitspontaneousAFbutthatrapidatrialpacingunmasked anincreasedvulnerabilitytoAFinthesemicecomparedwithwild-typemice.Rapidatrialpacingresulted inincreasedCa 2+ /calmodulin-dependentproteinkinaseII(CaMKII)phosphorylationofRyR2,whileboth pharmacologicandgeneticinhibitionofCaMKIIpreventedAFinducibilityinRyr2 R176Q/+ mice.Thisresult