Phospholemman-dependent regulation of the cardiac Na/K-ATPase activity is modulated by inhibitor-1 sensitive type-1 phosphatase

Ali El-Armouche, Katrin Wittköpper, William Fuller, Jacqueline Howie, Michael J Shattock, Davor Pavlovic

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)


Cardiac Na/K-ATPase (NKA) is regulated by its accessory protein phospholemman (PLM). Whereas kinase-induced PLM phosphorylation has been shown to mediate NKA stimulation, the role of endogenous phosphatases is presently unknown. We investigated the role of protein phosphatase-1 (PP-1) on PLM phosphorylation and NKA activity in rat cardiomyocytes and failing human hearts. Incubation of rat cardiomyocytes with the chemical PP-1/PP-2A inhibitor okadaic acid or the specific PP-1-inhibitor peptide (I-1ct) identified PLM phosphorylation at Ser-68 as the main substrate for PP-1. Moreover, myocytes adenovirally overexpressing PP-1 inhibitor-1 protein (I-1,Ad-I-1/eGFP) showed a 70% increase in PLM Ser-68 phosphorylation and 65% increase in NKA current, compared with enhanced green fluorescence protein (eGFP)-infected controls (Ad-eGFP), using Western blotting and voltage clamping, respectively. Notably, in left ventricular myocardium from patients with heart failure, PLM Ser-68 phosphorylation was ≈ 50% lower (n=7) than in nonfailing controls (n=7). We provide the first physiological and biochemical evidence that PLM phosphorylation and cardiac Na/K-ATPase activity are negatively regulated by PP-1 and that this regulatory mechanism could be counteracted by I-1. This novel mechanism is markedly perturbed in failing hearts favoring PLM dephosphorylation and NKA deactivation and thus may contribute to maladaptive hypertrophy and arrhythmogenesis via chronically higher intracellular Na and Ca concentrations.

Original languageEnglish
Pages (from-to)4467-75
Number of pages9
JournalFASEB Journal
Issue number12
Publication statusPublished - Dec 2011


  • Animals
  • Cardiomyopathy, Dilated
  • Cells, Cultured
  • Heart Failure
  • Humans
  • Membrane Proteins
  • Models, Biological
  • Myocytes, Cardiac
  • Phosphoproteins
  • Phosphorylation
  • Protein Phosphatase 1
  • Proteins
  • Rats
  • Recombinant Proteins
  • Signal Transduction
  • Sodium-Potassium-Exchanging ATPase


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