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Calcium Signals Alter the Mobility and Localization of CaMKIIδ in Cardiomyocytes

Ca2+‐calmodulin dependent protein kinase II δ (CaMKIIδ) is an important regulator of cardiac myocyte ion channels, Ca2+ regulation, contraction and transcriptional control; and its activity is upregulated in pathological states. CaMKIIδ has two main splice variants (δB and δC), which differ only by a nuclear localization sequence, so δB is more concentrated in the nucleus. While activity‐triggered translocation of neuronal CaMKIIα to dendritic spines is established as part of memory formation, very little is known about the spatiotemporal dynamics of CaMKIIδ activation. Prevailing views have been that cardiac CaMKII forms extremely stable dodecamers anchored at target‐rich loci and displays very little mobility (partially due to its size). We tested this using adenovirally‐expressed δC‐GFP and δB‐GFP and fluorescence recovery after photobleaching (FRAP). We found that δC‐GFP is remarkably mobile in the cytoplasm (Tau 11.09±0.27s) in resting rabbit cardiac myocytes. Moreover calcium chelation with BAPTA slowed, but 0.5 Hz pacing increased recovery kinetics (Tau 17.08±1.7 and 8.76±0.42s, respectively). δB‐GFP had similar differences as δC‐GFP in mobility under resting, BAPTA and paced conditions (Tau of 11.41±0.61, 19.17±2.5, and 10.04±0.59s). Autonomous δCT287D‐GFP moved rapidly even without pacing (Tau 9.90±0.41s). Calcium effects on nuclear FRAP followed a similar pattern, but recovery was significantly slower (Tau at rest 70.2±4.5s and 56.68±2.2s for δC‐GFP and δB‐GFP). The recovery plateau in the nucleus was also only 0.394±0.02 and 0.105±0.01 for δC‐GFP and δB‐GFP respectively (vs. 0.865±0.01 and 0.824±0.01 in cytosol), indicating a significant non‐mobile fraction of CaMKIIδ in the nucleus. Immunocytochemistry revealed pacing drives endogenous CaMKIIδ out of the nucleus and away from the Z‐lines. Nuclear localization of endogenous CaMKII was even further decreased in resting heart failure rabbit myocytes compared to age matched controls. These results indicate that CaMKIIδ activation promotes its mobility and suggest that CaMKII translocation may be an essential component of signal spread in cardiomyocytes.