Calmodulin (CaM) binding to cardiac ryanodine receptor (RyR2) (CaM-RyR2) is a critical regulator of SR Ca release. Our recent studies indicated that CaM-RyR2 binding affinity is reduced in pathological conditions. However, the roles of CaM released from RyR2 are unknown. Here, we tested whether RyR2-dissociated CaM play a pivotal role in pathological cardiac hypertrophy. Results: First, we tested whether treatment with angiotensin II (AngII), which stimulates pathologic cardiac hypertrophy, reduced CaM-RyR2 binding and whether CaM moves to nucleus using immunofluorescence. After AngII exposure, there are significant shifts of CaM from RyR2 to nucleus. To further test whether this nuclear CaM accumulation comes from CaM-RyR2, we used dantrolene, which is known to restore the CaM-RyR2 binding affinity, or suramin, which completely deplete CaM from RyR2. Treatment with Dantrolene and AngII dramatically reduced nuclear CaM accumulation vs. AngII alone. On the other hands, suramin significantly increased the nuclear CaM accumulation, suggesting that nuclear CaM accumulation comes from RyR2-CaM. To gain further information about this relation, we measured the kinetics of CaM movement after treatment with AngII. After exposure of AngII, CaM-RyR2 dissociation was faster than nuclear CaM association rate, indicating that CaM-RyR2 dissociation was the trigger for nuclear CaM translocation. Conclusions: Nuclear accumulation of CaM, which came from RyR2-dissociated CaM, may be an important step in driving pathological cardiac hypertrophy.
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