AIMS: The heart contraction is controlled by the @entity141 -induced @entity141 release (CICR) between L-type Ca(2+   )channels and @entity8452 receptors (RyRs). The @entity1140 -binding protein @entity12573 binds to @entity13868 subunits, but its role in stabilizing @entity13868 function has been debated for long. Recent reports of high-resolution @entity13868 structure show that the HD2 domain that binds to the SPRY2 domain of neighbouring subunit in FKBP-bound @entity13868 is detached and invisible in FKBP-null @entity23963 . The present study was to test the consequence of @entity12573 absence on the in situ activation of @entity23963 . METHODS AND RESULTS: Using whole-cell patch-clamp combined with confocal imaging, we applied a near threshold depolarization to activate a very small fraction of LCCs, which in turn activated @entity13868 Ca(2+   )sparks stochastically. @entity12573 -knockout and @entity1140 / @entity3446 treatments increased spark frequency and LCC- @entity13868 coupling fidelity without altering LCC open probability. Neither @entity1140 nor @entity3446 further altered LCC- @entity13868 coupling fidelity in @entity12573 -knockout cells. In loose-seal patch-clamp experiments, the LCC- @entity13868 signalling kinetics, indexed by the delay for a LCC sparklet to trigger a @entity13868 spark, was accelerated after @entity12573 knockout and @entity1140 / @entity3446 treatments. These results demonstrated that RyRs became more sensitive to @entity141 triggers without @entity12573 . @entity3044 (1    M) further accelerated the LCC- @entity13868 signalling in @entity12573 -knockout cells. The synergistic sensitization of RyRs by catecholaminergic signalling and @entity12573 dysfunction destabilized the CICR system, leading to chaotic Ca(2+   )waves and @entity943 . CONCLUSION: @entity12573 keeps the RyRs from over-sensitization, stabilizes the potentially regenerative CICR system, and thus may suppress the life-threatening arrhythmogenesis.

Sensitized signalling between L-type @entity141 channels and @entity8452 receptors in the absence or inhibition of XXXX in cardiomyocytes.

@entity8452 :: ('MESH:D012433', 'Chemical') :: ['ryanodine'] @entity12573 :: ('2281', 'Gene') :: ['FKBP12.6'] @entity13868 :: ('6261', 'Gene') :: ['RyR', 'RyR1'] @entity3446 :: ('MESH:D020123', 'Chemical') :: ['rapamycin'] @entity3044 :: ('MESH:D007545', 'Chemical') :: ['Isoproterenol'] @entity23963 :: ('6262', 'Gene') :: ['RyR2'] @entity1140 :: ('MESH:D016559', 'Chemical') :: ['FK506'] @entity141 :: ('CHEBI:29108', 'Chemical') :: ['Ca(2+   )', 'Ca(2+)'] @entity943 :: ('MESH:D001145', 'Disease') :: ['ventricular arrhythmias']
@entity12573 :: (2281,Gene) :: ['FKBP12.6']
