Stress-driven cardiac calcium mishandling via a kinase-to-kinase crosstalk

Figures

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  Fig. 1. A representation of normal Ca2+ cycling in cardiomyocytes and stress kinase JNK2-mediated CaMKIIδ-dependent SR Ca2+ mishandling and maladaptive cardiac dysfunction. Physiological and pathological regulation of Ca2+ cycling in cardiomyocytes and activated CaMKIIδ-dependent dysregulation of RyR2 as well as other ion channels (i.e., NaV1.5 and KV), which lead to enhanced diastolic SR Ca2+ leak, triggered arrhythmic Ca2+ activates (sparks and waves), DADs, and cardiac dysfunction. A JNK2-driven CaMKIIδ-dependent diastolic leak–uptake relationship also enhances triggered arrhythmic activities. JNK2 c-jun N-terminal kinase, CaMKIIδ Ca2+/calmodulin-kinase type-II delta isoform, NaV1.5a voltage-gated sodium channel isoform 1.5-alpha, LTCC L-type Ca2+ channels, OX oxidation, SR sarcoplasmic reticulum, PLB phospholamban, SERCA2 SR Ca2+-ATPase, DADs delayed afterdepolarizations, P phosphorylation, RyR2 ryanodine receptor type-2, NCX sodium-calcium exchanger

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  Fig. 2. A schematic outline of underlying mechanisms of CaMKIIδ activation and its functional consequences. Stressors (i.e., aging, alcohol, HF, and MI) lead to the activation of signal transduction pathways and the JNK kinase family (JNKs), which enhance CaMKIIδ activity through post-translational modifications including S-nitrosylation, O-GlcNacylation, oxidation, or direct phosphorylation on the regulatory domain of CaMKIIδ. Activated CaMKIIδ phosphorylates its downstream protein targets (i.e., RyR2, LTCC, and PLB) that are central to calcium homeostasis in the cardiomyocyte and in abnormal calcium dynamics in the development of maladaptive cardiac remodeling under pathological conditions (i.e., arrhythmia and HF). Auto-P autophosphorylation, Ca2+/CaM calmodulin, CVDs cardiovascular diseases, HF heart failure, LTCC L-type Ca2+ channels, MI myocardial infarction, NO nitric oxide, O-GlcNA O-linked-N-acetylglucosaminylation (O-GlcNAcylation), PLB phospholamban, RNS reactive nitrogen species, ROS reactive oxygen species, RyR2 ryanodine receptor type-2, S-Nitro s-nitrosylation.

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  Fig. 3. JNK2 kinase is schematically shown as an essential transcriptional regulator of CaMKIIδ expression. The JNK2 downstream transcription factors c-jun and ATF2 both bind to the CaMKIIδ gene promoter, but c-jun is a key transcription factor regulating the basal level expression of CaMKIIδ and a crucial transcriptional enhancer of CaMKIIδ expression in response to certain stress stimuli. ATF2 activating transcription factor 2