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(Circulation Research. 2006;99:1376.)
© 2006 American Heart Association, Inc.

Cellular Biology

Phospholemman Phosphorylation Mediates the Protein Kinase C–Dependent Effects on Na⁺/K⁺ Pump Function in Cardiac Myocytes

Fei Han, Julie Bossuyt, Sanda Despa, Amy L. Tucker, Donald M. Bers

From the Department of Physiology (F.H., J.B., S.D., D.M.B.), Loyola University Chicago, Maywood, Ill; and University of Virginia (A.L.T.), Charlottesville, Va.

Correspondence to Donald M. Bers, PhD, Department of Physiology, Loyola University Chicago, Stritch School of Medicine, 2160 S First Ave, Maywood, IL 60153. E-mail dbers{at}lumc.edu

Because phospholemman (PLM) regulates the Na⁺/K⁺ pump (NKA) and is a major cardiac phosphorylation target for both protein kinase A (at Ser68) and protein kinase C (PKC) (at both Ser63 and Ser68), we evaluated whether PLM mediates the PKC-dependent regulation of NKA function and protein kinase A/PKC crosstalk in ventricular myocytes. PKC was activated by PDBu (300 nmol/L), and we measured NKA-mediated [Na⁺]_i decline (fluorescence measurements) and current (I_pump) (voltage clamp). In wild-type mouse myocytes, PDBu increased PLM phosphorylation at Ser63 and Ser68, I_pump (both at 10 and 100 mmol/L Na⁺ in the pipette solution) and maximal NKA-mediated Na⁺ extrusion rate (V_max) from 7.9±1.1 to 12.7±1.9 mmol·L^–1 per minute without altering NKA affinity for internal Na⁺ (K_0.5). In PLM knockout mice, PDBu had no effect on either V_max or K_0.5. After pretreatment with isoproterenol (ISO) (1 µmol/L), PDBu still increased the NKA V_max and PLM phosphorylation at Ser63 and Ser68. Conversely, after pretreatment with PDBu, ISO further increased the Na⁺ affinity of NKA and phosphorylation at Ser68, as it did alone without PDBu. The final NKA activity was independent of the application sequence. The NKA activity in PLM knockout myocytes, after normalizing the protein level, was similar to that after PDBu and ISO treatment. We conclude that (1) PLM mediates the PKC-dependent activation of NKA function in cardiac myocytes, (2) PDBu and ISO effects are additive in the mouse (affecting mainly V_max and K_0.5, respectively), and (3) PDBu and ISO combine to activate NKA in wild-type to the level found in the PLM knockout mouse.

Key Words: Na⁺ pump • phospholemman • PKA • PKC

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