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

Ali El-Armouche, Katrin Wittkoepper, William Fuller, Jacqueline Howie, Michael J. Shattock (Lead / Corresponding author), Davor Pavlovic

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    Abstract

    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 similar to 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.-El-Armouche, A., Wittkopper, K., Fuller, W., Howie, J., Shattock, M. J., Pavlovic, D. Phospholemman-dependent regulation of the cardiac Na/K-ATPase activity is modulated by inhibitor-1 sensitive type-1 phosphatase. FASEB J. 25, 4467-4475 (2011). www.fasebj.org

    Original languageEnglish
    Pages (from-to)4467-4475
    Number of pages9
    JournalFASEB Journal
    Volume25
    Issue number12
    Early online date17 Aug 2011
    DOIs
    Publication statusPublished - Dec 2011

    Keywords

    • Sodium pump
    • FXYD1
    • Heart failure
    • beta-adrenergic signaling

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