Elsevier

Gene

Volume 590, Issue 1, 15 September 2016, Pages 90-96
Gene

Gene wiki review
PRKCE gene encoding protein kinase C-epsilon—Dual roles at sarcomeres and mitochondria in cardiomyocytes

https://doi.org/10.1016/j.gene.2016.06.016Get rights and content

Highlights

  • PKCε action in cardiomyocytes is spatiotemporally regulated.

  • PKCε acts on sarcomeric targets and regulates cardiac contraction and hypertrophy.

  • PKCε targets mitochondria to modulate metabolism and elicit cardioprotection.

Abstract

Protein kinase C-epsilon (PKCε) is an isoform of a large PKC family of enzymes that has a variety of functions in different cell types. Here we discuss two major roles of PKCε in cardiac muscle cells; specifically, its role in regulating cardiac muscle contraction via targeting the sarcomeric proteins, as well as modulating cardiac cell energy production and metabolism by targeting cardiac mitochondria. The importance of PKCε action is described within the context of intracellular localization, as substrate selectivity and specificity is achieved through spatiotemporal targeting of PKCε. Accordingly, the role of PKCε in regulating myocardial function in physiological and pathological states has been documented in both cardioprotection and cardiac hypertrophy.

Section snippets

PRKCE structure and activation in cardiomyocytes

The PRKCE gene (Ensembl ID: ENSG00000171132 WTSI/EMBL-EBI, 2015) encodes protein kinase C epsilon (PKCε, Uniprot ID: Q02156 EMBL-EBI, 2002). PKC is comprised of a family of serine-threonine kinases that contains thirteen PKC isoforms which differ in primary structure, protein expression, subcellular localization, and modes of activation (Dekker and Parker, 1994). PKCε is a PKC isoform highly expressed in adult cardiomyocytes (Rybin and Steinberg, 1994, Disatnik et al., 1994, Bogoyevitch et al.,

Sarcomeric targeting for modulation of cardiac contractile function and hypertrophy

Upon activation by various cellular stimuli, one target of PKCε translocation is to cardiac sarcomeres where PKCε plays a role in contractility of the myocardium (see Fig. 2). PKCε docks at cardiac Z-lines with an EC50 of 86 nM, likely via RACK2 (Huang and Walker, 2004), and PKCε binds to syndecan-4 (syn-4) and focal adhesion complexes at cardiac costameres (VanWinkle et al., 2002, Heidkamp et al., 2003); in both cases positioning PKCε to phosphorylate sarcomeric targets. Though not yet

Mitochondrial targeting for modulation of metabolic pathways and mitochondrial function

The PKC hypothesis of cardioprotection was first introduced by JM Downey in 1994 (Ytrehus et al., 1994), which spawned a series of exciting studies investigating isoform-specific effects of PKC in protection against ischemic injury. PKCε has been strongly implicated in preconditioning (PC), and PKCε acting at mitochondria is the most well-described cardioprotective paradigm. Ping et al. conducted a comprehensive study examining PKC isoform-specific profiles following five different PC regimens

Conclusion

Findings presented here clearly demonstrate a prominent role for the ε isoform of PKC acting on sarcomeres and mitochondria in cardiac health and disease. Translation of these findings into treatment for ischemic injury and heart failure will require the integration of dynamic actions of PKCε at each subcellular location into one comprehensive picture. Innovative research aimed at elucidating the endogenous positioning and presentation of PKCε have come from Daria Mochley-Rosen and colleagues

Acknowledgements

The authors are supported by the National Institutes of Health (R37 HL063901, R01 HL129723, and U54 GM114833).

This review and the corresponding Gene Wiki article are written as part of the Cardiac Gene Wiki Review series—a series resulting from a collaboration between the journal GENE, the Gene Wiki Initiative, and the NIH BD2K Initiative. The Cardiac Gene Wiki Initiative is supported by National Institutes of Health (R01 GM089820 and U54 GM114833). Additional support for Gene Wiki Reviews is

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