Frequency-encoding Thr17 phospholamban phosphorylation is independent of Ser16 phosphorylation in cardiac myocytes

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Abstract

Both Ser16 and Thr17 of phospholamban (PLB) are phosphorylated, respectively, by caMP-dependent protein kinase (PKA) and Ca2+/calmodulin-dependent protein kinase II (CaMKII). PLB phosphorylation relieves cardiac sarcoplasmic reticulum Ca2+ pump from inhibition by PLB. Previous studies have suggested that phosphorylation of Ser16 by PKA is a prerequisite for Thr17 phosphorylation by CaMKII and is essential to the relaxant effect of β-adrenergic stimulation. To determine the role of Thr17 PLB phosphorylation, we investigated the dual-site phosphorylation of PLB in isolated adult rat cardiac myocytes in response to β1-adrenergic stimulation or electrical field stimulation (0.1-3 Hz) or both. A β1-adrenergic agonist, norepinephrine (10-9-10-6 M), in the presence of an α1-adrenergic antagonist, prazosin (10-6 M), selectively increases the PKA-dependent phosphorylation of PLB at Ser16 in quiescent myocytes. In contrast, electrical pacing induces an opposite phosphorylation pattern, selectively enhancing the CaMKII-mediated Thr17 PLB phosphorylation in a frequency-dependent manner. When combined, electric stimulation (2 Hz) and β1-adrenergic stimulation lead to dual phosphorylation of PLB and exert a synergistic effect on phosphorylation of Thr17 but not Ser16. Frequency-dependent Thr17 phosphorylation is closely correlated with a decrease in 50% relaxation time (t50) of cell contraction, which is independent of, but additive to, the relaxant effect of Ser16 phosphorylation, resulting in hastened contractile relaxation at high stimulation frequencies. Thus, we conclude that in intact cardiac myocytes, phosphorylation of PLB at Thr17 occurs in the absence of prior Ser16 phosphorylation, and that frequencydependent Thr17 PLB phosphorylation may provide an intrinsic mechanism for cardiac myocytes to adapt to a sudden change of heart rate.

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Hagemann, D., Kuschel, M., Kuramochi, T., Zhu, W., Cheng, H., & Xiao, R. P. (2000). Frequency-encoding Thr17 phospholamban phosphorylation is independent of Ser16 phosphorylation in cardiac myocytes. Journal of Biological Chemistry, 275(29), 22532–22536. https://doi.org/10.1074/jbc.C000253200

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