Rationale: Loss-of function mutations in HERG @entity972 channels underlie @entity1162 ( @entity1162 ) type 2 (LQT2), and are associated with fatal @entity1165 . Previously, most studies focused on plasmamembrane-related pathways involved in arrhythmogenesis in @entity1162 , while pro-arrhythmic changes in intracellular @entity141 handling remained unexplored. Objective: We investigated the remodeling of @entity141 homeostasis in ventricular cardiomyocytes derived from transgenic @entity95 model of LQT2 in order to determine whether these changes contribute to triggered activity in the form of @entity8658 ( @entity8658 ). Methods and Results: Confocal @entity141 imaging revealed decrease in amplitude of @entity141 transients and SR @entity141 content in LQT2 myocytes. Experiments using SR-entrapped @entity141 indicator demonstrated enhanced RyR-mediated SR @entity141 leak in LQT2 cells. Western blot analyses showed increased phosphorylation of RyR in LQT2 myocytes vs. controls. Co-immunoprecipitation experiments demonstrated loss of protein phosphatases type 1 and type 2 from the RyR complex. Stimulation of LQT2 cells with b-adrenergic agonist @entity3044 resulted in prolongation of the plateau of action potentials accompanied by aberrant @entity141 releases and @entity8658 , which were abolished by inhibition of CaMKII. Computer simulations showed that late aberrant @entity141 releases caused by @entity2915 promote @entity8658 and underlie the enhanced triggered activity through increased forward mode of @entity68192 . Conclusions: Hyperactive, hyperphosphorylated RyRs due to reduced local phosphatase activity enhance triggered activity in @entity31868 . @entity8658 are promoted by aberrant RyR-mediated @entity141 releases that are present despite a reduction of sarcoplasmic reticulum (SR) content. Those releases increase forward mode @entity68192 , thereby slowing repolarization and enabling L-type @entity141 current reactivation.

Hyperphosphorylation of RyRs Underlies Triggered Activity in Transgenic XXXX Model of LQT2 Syndrome.

@entity8658 :: ('MESH:C580055', 'Disease') :: ['EADs', 'early afterdepolarizations'] @entity1165 :: ('MESH:D017180', 'Disease') :: ['ventricular tachyarrhythmia'] @entity95 :: ('9986', 'Species') :: ['rabbit'] @entity68192 :: ('100328570(Tax:9986)', 'Gene') :: ['NCX1'] @entity31868 :: ('MESH:C563614', 'Disease') :: ['LQT2 syndrome'] @entity3044 :: ('MESH:D007545', 'Chemical') :: ['isoproterenol'] @entity2915 :: ('MESH:D006948', 'Disease') :: ['RyR hyperactivity'] @entity972 :: ('MESH:D011188', 'Chemical') :: ['potassium'] @entity141 :: ('CHEBI:29108', 'Chemical') :: ['Ca2+', 'Ca(2+)'] @entity1162 :: ('MESH:D008133', 'Disease') :: ['LQTS', 'long QT syndrome']
@entity95 :: (9986,Species) :: ['Rabbit']
