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CaMKIIδ and cardiomyocyte Ca(2+) signalling new perspectives on splice variant targeting
James R Bell1, Antonia J A Raaijmakers1, Johannes V Janssens1
1Department of Physiology, University of Melbourne, Victoria, Australia.
Abstract:
Control of cardiomyocyte cytosolic Ca(2+) levels is crucial in determining inotropic status and ischemia/reperfusion stress response. Responsive to fluctuations in cellular Ca(2+), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a serine/threonine kinase integral to the processes regulating cardiomyocyte Ca(2+) channels/transporters. CaMKII is primarily expressed either in the δB or δC splice variant forms, which may mediate differential influences on cardiomyocyte function and pathological response mechanisms. Increases in myocyte Ca(2+) levels promote the binding of a Ca(2+)/calmodulin complex to CaMKII, to activate the kinase. Activity is also maintained through a series of post-translational modifications within a critical region of the regulatory domain of the protein. Recent data indicate that the post-translational modification status of CaMKIIδB/δC variants may have an important influence on reperfusion outcomes. This study provided the first evidence that the specific type of CaMKII post-translational modification has a role in determining target selectivity of downstream Ca(2+) transporters. The study was also able to demonstrate that the phosphorylated form of CaMKII closely co-localizes with CaMKIIδB in the nuclear/myofilament fraction, contrasting with a co-enrichment of oxidized CaMKII in the membrane fraction with CaMKIIδC . It has also been possible to conclude that a hyper-phosphorylation of CaMKII (Thr287) in reperfused hearts represents a hyper-activation of the CaMKIIδB , which exerts anti-arrhythmic actions through an enhanced capacity to selectively increase sarcoplasmic reticulum Ca(2+) uptake and maintain cytosolic Ca(2+) levels. This suggests that suppression of global CaMKIIδ may not be an efficacious approach to developing optimal pharmacological interventions for the vulnerable heart.
Insights
Calcium/calmodulin-dependent protein kinase II (CaMKII) variants influence heart function. Specific CaMKII modifications, particularly hyper-phosphorylation of CaMKIIδB, show anti-arrhythmic effects by improving calcium handling during reperfusion.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Biochemistry
Background:
- Cytosolic Ca(2+) homeostasis is vital for cardiomyocyte function and response to ischemia/reperfusion.
- Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) regulates Ca(2+) channels/transporters and exists as δB and δC splice variants.
- Post-translational modifications of CaMKII influence its activity and impact on cardiac pathology.
Purpose of the Study:
- To investigate the role of CaMKII post-translational modifications in determining target selectivity of Ca(2+) transporters.
- To examine the differential localization and function of CaMKIIδB and CaMKIIδC variants under stress conditions.
- To elucidate the impact of CaMKII hyper-phosphorylation on reperfusion outcomes and cardiac rhythm.
Main Methods:
- Co-localization studies of modified CaMKII variants (phosphorylated, oxidized) with CaMKIIδB and CaMKIIδC in subcellular fractions.
- Analysis of CaMKII activity and its association with Ca(2+) transporters in reperfused heart models.
- Assessment of anti-arrhythmic effects related to CaMKII modifications and calcium handling.
Main Results:
- Specific CaMKII post-translational modifications dictate selectivity for downstream Ca(2+) transporters.
- Phosphorylated CaMKIIδB co-localizes with nuclear/myofilament fractions, while oxidized CaMKIIδC associates with the membrane fraction.
- Hyper-phosphorylation of CaMKII (Thr287) in reperfused hearts activates CaMKIIδB, enhancing sarcoplasmic reticulum Ca(2+) uptake and maintaining cytosolic Ca(2+) levels, exerting anti-arrhythmic effects.
Conclusions:
- CaMKII post-translational modification status is critical for its functional effects on cardiomyocyte Ca(2+) handling.
- CaMKIIδB and CaMKIIδC variants exhibit distinct localization and functional roles influenced by their modification state.
- Targeting CaMKIIδB hyper-phosphorylation may offer a therapeutic strategy for protecting the heart during reperfusion, suggesting global CaMKIIδ suppression may be less effective.
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