UNASSIGNED: A hallmark of @entity1 and experimental @entity712 is @entity1893 (SR) @entity9495 -uptake reflecting impaired contractile function. This is at least partially attributed to dephosphorylation of phospholamban by increased @entity13977 ( @entity13977 ) activity. Indeed inhibition of @entity13977 by transgenic overexpression or gene-transfer of constitutively active @entity23348 improved @entity9495 -cycling, preserved function and decreased @entity82 in small and large animal models of @entity712 , suggesting that @entity23348 may represent a potential therapeutic target. We recently identified a novel @entity1 polymorphism ( @entity68842 ) in the @entity23348 gene with a frequency of 7% in either normal or @entity712 @entity1 . @entity19 , harboring cardiac-specific expression of @entity68842 @entity23348 , exhibited decreases in contractility, @entity9495 -kinetics and SR @entity9495 -load. These depressive effects were relieved by @entity3044 stimulation. Furthermore, stress conditions (2Hz +/- @entity8670 ) induced increases in @entity9495 -sparks, @entity9495 -waves (60% of @entity68842 versus 20% in wild types) and after-contractions (76% of @entity68842 versus 23% of wild types) in mutant cardiomyocytes. Similar findings were obtained by acute expression of the @entity68842 variant in adult cardiomyocytes in the absence or presence of endogenous @entity23348 . The underlying mechanisms included reduced binding of mutant @entity23348 to @entity13977 , increased @entity13977 activity, and dephosphorylation of phospholamban at Ser16 and Thr17. However, phosphorylation of the @entity8452 receptor at Ser2808 was not altered while phosphorylation at Ser2814 was increased, consistent with increased activation of @entity9495 /calmodulin-dependent protein kinase II (CaMKII), promoting aberrant SR @entity9495 -release. Parallel in vivo studies revealed that mutant @entity19 developed @entity1540 (including bigeminy, trigeminy and @entity1165 ), when challenged with @entity3044 . Inhibition of CaMKII activity by @entity14374 prevented the increased propensity to @entity943 . These findings suggest that the @entity1 @entity68842 @entity23348 variant impairs SR @entity9495 -cycling and promotes arrhythmogenesis under stress conditions, which may present an additional insult in the compromised function of @entity712 carriers.

@entity1 XXXX - @entity23348 impairs cardiac function and promotes @entity943 .

@entity1 :: ('9606', 'Species') :: ['human', 'patients'] @entity712 :: ('MESH:D006333', 'Disease') :: ['heart failure'] @entity82 :: ('MESH:D005355', 'Disease') :: ['fibrosis'] @entity23348 :: ('5502', 'Gene') :: ['inhibitor-1'] @entity1165 :: ('MESH:D017180', 'Disease') :: ['ventricular tachycardia'] @entity19 :: ('10090', 'Species') :: ['mice', 'Transgenic mice'] @entity8452 :: ('MESH:D012433', 'Chemical') :: ['ryanodine'] @entity13977 :: ('5464', 'Gene') :: ['PP1', 'protein phosphatase 1'] @entity3044 :: ('MESH:D007545', 'Chemical') :: ['isoproterenol'] @entity14374 :: ('MESH:C072105', 'Chemical') :: ['KN-93'] @entity8670 :: ('D007545', 'Chemical') :: ['Iso'] @entity1540 :: ('MESH:D018879', 'Disease') :: ['ventricular ectopy and complex ventricular arrhythmias'] @entity1893 :: ('MESH:D008228', 'Disease') :: ['deficient sarcoplasmic reticulum'] @entity943 :: ('MESH:D001145', 'Disease') :: ['arrhythmias'] @entity9495 :: ('D002118', 'Chemical') :: ['Ca'] @entity68842 :: ('p|SUB|G|109|E', 'ProteinMutation') :: ['G109E']
@entity68842 :: (p|SUB|G|109|E,ProteinMutation) :: ['G109E']
