Gene wiki reviewPRKCE gene encoding protein kinase C-epsilon—Dual roles at sarcomeres and mitochondria in cardiomyocytes
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
References (101)
- et al.
The mitochondrial permeability transition pore: molecular nature and role as a target in cardioprotection
J. Mol. Cell. Cardiol.
(2015) - et al.
Phosphorylation or glutamic acid substitution at protein kinase C sites on cardiac troponin I differentially depress myofilament tension and shortening velocity
J. Biol. Chem.
(2003) - et al.
Differential activation of protein kinase C isoforms by endothelin-1 and phenylephrine and subsequent stimulation of p42 and p44 mitogen-activated protein kinases in ventricular myocytes cultured from neonatal rat hearts
J. Biol. Chem.
(1994) - et al.
Protein kinase C—a question of specificity
Trends Biochem. Sci.
(1994) - et al.
Localization of protein kinase C isozymes in cardiac myocytes
Exp. Cell Res.
(1994) - et al.
Stimulus-dependent subcellular localization of activated protein kinase C; a study with acidic fibroblast growth factor and transforming growth factor-beta 1 in cardiac myocytes
J. Mol. Cell. Cardiol.
(1995) - et al.
PKC-delta and PKC-epsilon: foes of the same family or strangers?
J. Mol. Cell. Cardiol.
(2011) - et al.
Protein kinase C epsilon signaling complexes include metabolism- and transcription/translation-related proteins: complimentary separation techniques with LC/MS/MS
Mol. Cell. Proteomics
(2002) - et al.
A selective epsilon-protein kinase C antagonist inhibits protection of cardiac myocytes from hypoxia-induced cell death
J. Biol. Chem.
(1997) - et al.
Increased particulate partitioning of PKC epsilon reverses susceptibility of phospholamban knockout hearts to ischemic injury
J. Mol. Cell. Cardiol.
(2004)
New insights into the functional significance of the acidic region of the unique N-terminal extension of cardiac troponin I
Biochim. Biophys. Acta
HASF is a stem cell paracrine factor that activates PKC epsilon mediated cytoprotection
J. Mol. Cell. Cardiol.
Tissue angiotensin II during progression or ventricular hypertrophy to heart failure in hypertensive rats; differential effects on PKC epsilon and PKC beta
J. Mol. Cell. Cardiol.
Phosphorylation specificities of protein kinase C isozymes for bovine cardiac troponin I and troponin T and sites within these proteins and regulation of myofilament properties
J. Biol. Chem.
A protein kinase C translocation inhibitor as an isozyme-selective antagonist of cardiac function
J. Biol. Chem.
Protein kinase C-epsilon is responsible for the protection of preconditioning in rabbit cardiomyocytes
J. Mol. Cell. Cardiol.
Cardiac troponin I mutants. Phosphorylation by protein kinases C and A and regulation of Ca(2 +)-stimulated MgATPase of reconstituted actomyosin S-1
J. Biol. Chem.
Epac and phospholipase Cepsilon regulate Ca2 + release in the heart by activation of protein kinase Cepsilon and calcium-calmodulin kinase II
J. Biol. Chem.
Differential regulation of protein kinase C isoforms in isolated neonatal and adult rat cardiomyocytes
J. Biol. Chem.
Localization and kinetics of protein kinase C-epsilon anchoring in cardiac myocytes
Biophys. J.
Partial replacement of cardiac troponin I with a non-phosphorylatable mutant at serines 43/45 attenuates the contractile dysfunction associated with PKCepsilon phosphorylation
J. Mol. Cell. Cardiol.
Early inactivation of PKCepsilon associates with late mitochondrial translocation of bad and apoptosis in ventricle of septic rat
J. Surg. Res.
Protein kinase C (PKC) mediated interaction between conexin43 (Cx43) and K(+)(ATP) channel subunit (Kir6.1) in cardiomyocyte mitochondria: implications in cytoprotection against hypoxia induced cell apoptosis
Cell. Signal.
Reduced cardiac CapZ protein protects hearts against acute ischemia-reperfusion injury and enhances preconditioning
J. Mol. Cell. Cardiol.
Molecular mechanism underlying adenosine receptor-mediated mitochondrial targeting of protein kinase C
Biochim. Biophys. Acta
Protein kinase C-epsilon (PKC-epsilon): its unique structure and function
J. Biochem.
An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore
Proc. Natl. Acad. Sci. U. S. A.
Muscle ring finger protein-1 inhibits PKC{epsilon} activation and prevents cardiomyocyte hypertrophy
J. Cell Biol.
Mitochondrial PKCepsilon and MAPK form signaling modules in the murine heart: enhanced mitochondrial PKCepsilon-MAPK interactions and differential MAPK activation in PKCepsilon-induced cardioprotection
Circ. Res.
Protein kinase Cepsilon interacts with and inhibits the permeability transition pore in cardiac mitochondria
Circ. Res.
Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death
Nat. Cell Biol.
Characterization of protein kinase C isotype expression in adult rat heart. Protein kinase C-epsilon is a major isotype present, and it is activated by phorbol esters, epinephrine, and endothelin
Circ. Res.
The nitric oxide hypothesis of late preconditioning
Basic Res. Cardiol.
Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition
Cell Cycle
Mitochondrial import of PKCepsilon is mediated by HSP90: a role in cardioprotection from ischaemia and reperfusion injury
Cardiovasc. Res.
Identification of εPKC targets during cardiac ischemic injury
Circ. J.
Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart
Science
Intramitochondrial signaling: interactions among mitoKATP, PKCepsilon, ROS, and MPT
Am. J. Physiol. Heart Circ. Physiol.
Sustained in vivo cardiac protection by a rationally designed peptide that causes epsilon protein kinase C translocation
Proc. Natl. Acad. Sci. U. S. A.
UniProtKB - Q02156 (KPCE_HUMAN)
The role of PKCepsilon-dependent signaling for cardiac differentiation
Histochem. Cell Biol.
Mitochondrial reactive oxygen species: which ROS signals cardioprotection?
Am. J. Physiol. Heart Circ. Physiol.
Dimers of mitochondrial ATP synthase form the permeability transition pore
Proc. Natl. Acad. Sci. U. S. A.
Protein kinase Cepsilon overexpression alters myofilament properties and composition during the progression of heart failure
Circ. Res.
The MLCK-mediated alpha1-adrenergic inotropic effect in atrial myocardium is negatively modulated by PKCepsilon signaling
Br. J. Pharmacol.
PKC-epsilon is upstream and PKC-alpha is downstream of mitoKATP channels in the signal transduction pathway of ischemic preconditioning of human myocardium
Am. J. Phys. Cell Physiol.
Differential activation of mitogen-activated protein kinase cascades and apoptosis by protein kinase C epsilon and delta in neonatal rat ventricular myocytes
Circ. Res.
Activation of focal adhesion kinase by protein kinase C epsilon in neonatal rat ventricular myocytes
Am. J. Physiol. Heart Circ. Physiol.
Myofilament anchoring of protein kinase C-epsilon in cardiac myocytes
J. Cell Sci.
Arachidonic acid stimulates protein kinase C-epsilon redistribution in heart cells
J. Cell Sci.
Cited by (18)
Analysis of Genetic Variability in the Argentine Polo Horse With a Panel of Microsatellite Markers
2021, Journal of Equine Veterinary ScienceCitation Excerpt :AHT4 (23.3 Mb, ECA24) is close (23.1 Mb) to ADCK1 gene (aarF domain containing kinase 1) that plays a critical role in muscle mitochondria homeostasis [19]. In addition, ASB2 (55.6 Mb, ECA15) is close (54.2 Mb) to PRKCE gene (protein kinase C epsilon), an isoform of PKC family of enzymes targeting sarcomeric proteins and mitochondria of cardiomyocytes, regulating cardiac muscle contraction and energy production [20]. In the considered period, the mean He of the 15 STR panel decreased significantly, but it was equal or lower than the mean Ho, in agreement with the low inbreeding coefficient.
The role of epsilon PKC in acute and chronic diseases: Possible pharmacological implications of its modulators
2016, Pharmacological ResearchCitation Excerpt :When these channels are open they attenuates the lethal injury associated with Ca2+ overload in the cells after ischemia [48]. Other proposed mechanisms by which εPCK induce cardioprotection were its capacity in increasing nitric oxide (NO) production in rat heart by activating phosphatidylinositol-3-kinase (PI3-K) [49]; by inducing activation of NF-kappaB and AP-1 pathway in rabbit cardiomyocytes [50]; and by directly interacting with cardiac troponin I (cTnI) and cardiac troponin T (cTnT) in complex with troponin C (TnC) modulating contractile function [51]. Therefore, the role of εPCK in the IPC mechanism of protection has been well established in the past years.
Multiple Origins and Genomic Basis of Complex Traits in Sighthounds
2023, Molecular Biology and EvolutionMechanism of METTL3-Mediated m<sup>6</sup>A Modification in Cardiomyocyte Pyroptosis and Myocardial Ischemia–Reperfusion Injury
2023, Cardiovascular Drugs and TherapySkeletal Muscles of Sedentary and Physically Active Aged People Have Distinctive Genic Extrachromosomal Circular DNA Profiles
2023, International Journal of Molecular Sciences