Physiological and unappreciated roles of CaMKII in the heart

Abstract

In the cardiomyocyte, CaMKII has been identified as a nodal influencer of excitation-contraction and also excitation-transcription coupling. Its activity can be regulated in response to changes in intracellular calcium content as well as after several post-translational modifications. Some of the effects mediated by CaMKII may be considered adaptive, while effects of sustained CaMKII activity may turn into the opposite and are detrimental to cardiac integrity and function. As such, CaMKII has long been noted as a promising target for pharmacological inhibition, but the ubiquitous nature of CaMKII has made it difficult to target CaMKII specifically where it is detrimental. In this review, we provide a brief overview of the physiological and pathophysiological properties of CaMKII signaling, but we focus on the physiological and adaptive functions of CaMKII. Furthermore, special consideration is given to the emerging role of CaMKII as a mediator of inflammatory processes in the heart.

Keywords: Apoptosis; CaMKII; Calcium; Calmodulin; Cardiomyocyte; Inflammation.

Fig. 1

Alternative splicing of CaMKIIδ. Alternative exons (exons 14–16) in the pre-mRNA are depicted in gray. Differential alternative splicing gives rise to the different CaMKIIδ isoforms, which have different preferential cellular localizations and potentially different functions. Exon 14 contains a nuclear localization signal (NLS) and the serine (Ser322) adjacent to the NLS can posttranslationally be modified to affect nuclear localization

Fig. 2

CaMKII mediates chemokine expression and secretion in/from cardiomyocytes. In response to sustained catecholaminergic stress or ischemia/reperfusion (I/R) injury, CaMKII increases expression and potentially secretion of chemokine ligands such as CCL2/3 either dependent or independent of NF-κB signaling. This figure merely illustrates a very specific role of CaMKII and for a more general overview of all CaMKII functions, we would like to direct the reader to [31, 58]