Key result
A novel signal transduction pathway involving sequential activation of Epac, PLCepsilon, PKCepsilon, and CamKII regulates sarcoplasmic reticulum Ca2+ release downstream of beta-adrenergic receptor activation.
Identifies a novel beta-adrenergic signaling pathway involving Epac, PLCepsilon, PKCepsilon, and CamKII that regulates sarcoplasmic reticulum calcium release in cardiac myocytes.
Hypothesis-generating for beta-adrenergic Ca2+ regulation; prospective human studies needed before clinical translation.
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.
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Oestreich et al. (2008) studied Cardiac myocyte calcium signaling. beta-adrenergic receptor and Epac activation vs. PLCepsilon-/- myocytes was evaluated on Ca2+-induced Ca2+ release (CICR) and protein phosphorylation. A novel signal transduction pathway involving sequential activation of Epac, PLCepsilon, PKCepsilon, and CamKII regulates sarcoplasmic reticulum Ca2+ release downstream of beta-adrenergic receptor activation.
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