Epac and phospholipase Cepsilon regulate Ca2+ release in the heart by activation of protein kinase Cepsilon and calcium-calmodulin kinase II
- PMID: 18957419
- PMCID: PMC2615515
- DOI: 10.1074/jbc.M806994200
Epac and phospholipase Cepsilon regulate Ca2+ release in the heart by activation of protein kinase Cepsilon and calcium-calmodulin kinase II
Abstract
Recently, we identified a novel signaling pathway involving Epac, Rap, and phospholipase C (PLC)epsilon that plays a critical role in maximal beta-adrenergic receptor (betaAR) stimulation of Ca2+-induced Ca2+ release (CICR) in cardiac myocytes. Here we demonstrate that PLCepsilon phosphatidylinositol 4,5-bisphosphate hydrolytic activity and PLCepsilon-stimulated Rap1 GEF activity are both required for PLCepsilon-mediated enhancement of sarcoplasmic reticulum Ca2+ release and that PLCepsilon significantly enhances Rap activation in response to betaAR stimulation in the heart. Downstream of PLCepsilon hydrolytic activity, pharmacological inhibition of PKC significantly inhibited both betaAR- and Epac-stimulated increases in CICR in PLCepsilon+/+ myocytes but had no effect in PLCepsilon-/- myocytes. betaAR and Epac activation caused membrane translocation of PKCepsilon in PLCepsilon+/+ but not PLCepsilon-/- myocytes and small interfering RNA-mediated PKCepsilon knockdown significantly inhibited both betaAR and Epac-mediated CICR enhancement. Further downstream, the Ca2+/calmodulin-dependent protein kinase II (CamKII) inhibitor, KN93, inhibited betaAR- and Epac-mediated CICR in PLCepsilon+/+ but not PLCepsilon-/- myocytes. Epac activation increased CamKII Thr286 phosphorylation and enhanced phosphorylation at CamKII phosphorylation sites on the ryanodine receptor (RyR2) (Ser2815) and phospholamban (Thr17) in a PKC-dependent manner. Perforated patch clamp experiments revealed that basal and betaAR-stimulated peak L-type current density are similar in PLCepsilon+/+ and PLCepsilon-/- myocytes suggesting that control of sarcoplasmic reticulum Ca2+ release, rather than Ca2+ influx through L-type Ca2+ channels, is the target of regulation of a novel signal transduction pathway involving sequential activation of Epac, PLCepsilon, PKCepsilon, and CamKII downstream of betaAR activation.
Figures






Similar articles
-
Epac-mediated activation of phospholipase C(epsilon) plays a critical role in beta-adrenergic receptor-dependent enhancement of Ca2+ mobilization in cardiac myocytes.J Biol Chem. 2007 Feb 23;282(8):5488-95. doi: 10.1074/jbc.M608495200. Epub 2006 Dec 17. J Biol Chem. 2007. PMID: 17178726
-
Calcium-calmodulin kinase II mediates digitalis-induced arrhythmias.Circ Arrhythm Electrophysiol. 2011 Dec;4(6):947-57. doi: 10.1161/CIRCEP.111.964908. Epub 2011 Oct 18. Circ Arrhythm Electrophysiol. 2011. PMID: 22009705
-
The cAMP binding protein Epac modulates Ca2+ sparks by a Ca2+/calmodulin kinase signalling pathway in rat cardiac myocytes.J Physiol. 2007 Sep 1;583(Pt 2):685-94. doi: 10.1113/jphysiol.2007.133066. Epub 2007 Jun 28. J Physiol. 2007. PMID: 17599964 Free PMC article.
-
Epac in cardiac calcium signaling.J Mol Cell Cardiol. 2013 May;58:162-71. doi: 10.1016/j.yjmcc.2012.11.021. Epub 2012 Dec 7. J Mol Cell Cardiol. 2013. PMID: 23220153 Review.
-
Cardiac ryanodine receptor phosphorylation by CaM Kinase II: keeping the balance right.Front Biosci (Landmark Ed). 2009 Jun 1;14(13):5134-56. doi: 10.2741/3591. Front Biosci (Landmark Ed). 2009. PMID: 19482609 Review.
Cited by
-
Serotonin regulates 6-phosphofructo-1-kinase activity in a PLC-PKC-CaMK II- and Janus kinase-dependent signaling pathway.Mol Cell Biochem. 2013 Jan;372(1-2):211-20. doi: 10.1007/s11010-012-1462-0. Epub 2012 Sep 26. Mol Cell Biochem. 2013. PMID: 23010892
-
Arrhythmogenic Mechanisms in Heart Failure: Linking β-Adrenergic Stimulation, Stretch, and Calcium.Front Physiol. 2018 Oct 16;9:1453. doi: 10.3389/fphys.2018.01453. eCollection 2018. Front Physiol. 2018. PMID: 30374311 Free PMC article. Review.
-
Differential changes in cyclic adenosine 3'-5' monophosphate (cAMP) effectors and major Ca2+ handling proteins during diabetic cardiomyopathy.J Cell Mol Med. 2023 May;27(9):1277-1289. doi: 10.1111/jcmm.17733. Epub 2023 Mar 27. J Cell Mol Med. 2023. PMID: 36967707 Free PMC article.
-
Inhibition of ATP release from erythrocytes: a role for EPACs and PKC.Microcirculation. 2011 Feb;18(2):128-35. doi: 10.1111/j.1549-8719.2010.00073.x. Microcirculation. 2011. PMID: 21166931 Free PMC article.
-
Beta-Adrenergic Activation of the Inward Rectifier K+ Current Is Mediated by the CaMKII Pathway in Canine Ventricular Cardiomyocytes.Int J Mol Sci. 2024 Oct 29;25(21):11609. doi: 10.3390/ijms252111609. Int J Mol Sci. 2024. PMID: 39519160 Free PMC article.
References
-
- Jin, T. G., Satoh, T., Liao, Y., Song, C., Gao, X., Kariya, K., Hu, C. D., and Kataoka, T. (2001) J. Biol. Chem. 276 30301–30307 - PubMed
-
- Lopez, I., Mak, E. C., Ding, J., Hamm, H. E., and Lomasney, J. W. (2001) J. Biol. Chem. 276 2758–2765 - PubMed
-
- Shibatohge, M., Kariya, K., Liao, Y., Hu, C. D., Watari, Y., Goshima, M., Shima, F., and Kataoka, T. (1998) J. Biol. Chem. 273 6218–6222 - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Molecular Biology Databases
Miscellaneous