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.

Keywords: CaMKII; arrhythmias; calcium; cardiovascular disease; heart failure; kinase.

Figure 1

Multifunctional Ca²⁺ and calmodulin-dependent protein kinase II (CaMKII) structure and function. (a) The schematic of a CaMKII monomer shows that, upon binding Ca²⁺/calmodulin (CaM), the catalytic domain is released from the autoinhibitory pseudosubstrate and is enabled to phosphorylate its downstream targets. Several posttranslational modifications in the regulatory domain positively and negatively modulate CaMKII activity. Panel adapted from image created with Biorender.com. (b) In this structural depiction of CaMKII dodecameric holoenzymes, each domain is color coded as in panel a. Structures from the RCSB Protein Data Bank, rcsb.org (PDB IDs 5VLO, 2VN9, and 3SOA) (CC0 1.0). (c) CaMKIIδ undergoes alternative splicing to generate three prevalent variants in the heart. These variants differ only at the variable linker by inclusion or omission of exons 14 or 16.

Figure 2

Major known CaMKII signaling pathways in cardiomyocytes. Black arrows denote upstream stimulants, and faded arrows denote downstream pathological (red) and cardioprotective (blue) targets. Red phosphate groups denote phosphorylation by CaMKII. When known, arrow origin denotes the responsible splice variant. Abbreviations: CaMKII, multifunctional Ca²⁺ and calmodulin-dependent protein kinase II; CREB, cAMP response element–binding protein; H3, histone 3; HDAC4, histone deacetylase 4; HSF1, heat shock factor 1; I, current; IκB, inhibitor of nuclear factor kappa-B; IKK, inhibitor of nuclear factor kappa-B kinase; LTCC, L-type calcium channel; MEF2, myocyte-enhancer factor 2; MR, mineralocorticoid receptor; Myd88, myeloid differentiation primary response 88; NFAT, nuclear factor of activated T cells; NF-κB, nuclear factor kappa-B; NOX, nicotinamide adenine dinucleotide phosphate oxidase; PLN, phospholamban; Rac1, Rac family small GTPase 1; ROS, reactive oxygen species; RyR2, type 2 ryanodine receptor; SERCA2, sarco/endoplasmic reticulum calcium ATPase 2; TLR, toll-like receptor; UBE2T, ubiquitin-conjugating enzyme E2 T; UDP-GlcNAc, uridine diphosphate N-acetylglucosamine. Figure adapted from image created with Biorender.com.

Figure 3

Advantages and disadvantages of various CaMKII targeting strategies. Abbreviations: ASO, antisense oligonucleotide; CaMKII, multifunctional Ca²⁺ and calmodulin-dependent protein kinase II. CaMKII structure from Protein Data Bank, rcsb.org (PDB ID 3SOA) (CC0 1.0), rendered with Biorender.com.