CaMKII as a Therapeutic Target in Cardiovascular Disease

Abstract

CaMKII (the multifunctional Ca2+ and calmodulin-dependent protein kinase II) is a highly validated signal for promoting a variety of common diseases, particularly in the cardiovascular system. Despite substantial amounts of convincing preclinical data, CaMKII inhibitors have yet to emerge in clinical practice. Therapeutic inhibition is challenged by the diversity of CaMKII isoforms and splice variants and by physiological CaMKII activity that contributes to learning and memory. Thus, uncoupling the harmful and beneficial aspects of CaMKII will be paramount to developing effective therapies. In the last decade, several targeting strategies have emerged, including small molecules, peptides, and nucleotides, which hold promise in discriminating pathological from physiological CaMKII activity. Here we review the cellular and molecular biology of CaMKII, discuss its role in physiological and pathological signaling, and consider new findings and approaches for developing CaMKII therapeutics. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 63 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Molecular basis of interactions between CaMKII and α-actinin-2 that underlie dendritic spine enlargement

“…In our summary model (Figure 6), we suggest that docking to NMDARs is key for enabling α-actinin-2 to access the CaMKII regulatory segment but potentially other postsynaptic proteins that stably associate with CaMKII by occupying the substrate-binding groove of the kinase domain could also support activity-dependent increases in CaMKII-actinin association. There is potential for therapeutic inhibition of CaMKII (Pellicena & Schulman, 2014), and several leading peptide inhibitors of the kinase constitute pseudosubstrate sequences that occupy the substrate binding groove (Reyes Gaido et al, 2022). Our work suggests that developers of such inhibitors should be mindful of the potential for unexpected gain-of-function effects in inhibitors that increase access to the regulatory segment.…”

CaMKIIα as a Promising Drug Target for Ischemic Grey Matter

“…Albeit expressed throughout the whole body, CaMKII is most known for its neuronal and cardiac functions. Specifically, CaMKIIδ is highly expressed in cardiomyocytes contributing to cardiac placemaking [ 23 ] and calcium handling [ 27 ], whereas CaMKIIα and CaMKIIβ are predominantly expressed in neurons accounting for a remarkable 1–2% of total brain protein [ 28 ]. The latter emphasizes the importance of CaMKIIα/β as a signaling module, which was shown to mediate synaptic plasticity underlying learning and memory [ 20 , 29 , 30 , 31 ].…”

Genome-wide CRISPR screen reveals genetic modifiers of Ca2+-mediated cell death

“…Ca 2+ is known to modulate several modes of cell death including apoptosis, necrosis, autophagic death, and anoikis (10). Noteworthy known mechanisms of injury include i) mitochondrial permeability transition, where intracellular Ca 2+ is internalized by mitochondria and triggers mitochondrial dysfunction and rupture (11), ii) calpains and caspases, pro-death proteases that require Ca 2+ for induction (12)(13)(14), and iii) Ca 2+ /Calmodulin-dependent protein kinase II (CaMKII) hyperactivity-which leads to inflammation and activation of apoptotic and necroptotic programs (15)(16)(17)(18)(19). These pathways have become therapeutic targets with the hope to prevent tissue death.…”

“…Cyclosporine A) have failed in clinical trials (21,22). Similarly, caspase, calpain, and CaMKII inhibitors have been long sought to prevent cell death in ischemic, septic, and traumatic injury but adverse effects, lack of selectivity, and lack of efficacy have precluded their use in patients (19,(23)(24)(25)(26)(27). These examples highlight that our understanding of Ca 2+ in cell death is incomplete and that identifying other targetable mediators of Ca 2+ toxicity remains as a critical unmet need.…”