Phospholemman-mediated activation of Na/K-ATPase limits [Na]i and inotropic state during β-adrenergic stimulation in mouse ventricular myocytes

Sanda I Despa, Amy L. Tucker, Donald M. Bers

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

BACKGROUND - Cardiac Na/K-ATPase (NKA) regulates intracellular Na ([Na]i), which in turn affects intracellular Ca and thus contractility via Na/Ca exchange. Recent evidence shows that phosphorylation of the NKA-associated small transmembrane protein phospholemman (PLM) mediates β-adrenergic-induced NKA stimulation. METHODS AND RESULTS - Here, we tested whether PLM phosphorylation during β-adrenergic activation limits the rise in [Na]i, Ca transient amplitude, and triggered arrhythmias in mouse ventricular myocytes. In myocytes from wild-type (WT) mice, [Na]i increased on field stimulation at 2 Hz from 11.1±1.8 mmol/L to a plateau of 15.2±1.5 mmol/L. Isoproterenol induced a decrease in [Na]i to 12.0±1.2 mmol/L. In PLM knockout (PLM-KO) mice in which β-adrenergic stimulation does not activate NKA, [Na]i also increased at 2 Hz (from 10.4±1.2 to 17.0±1.5 mmol/L) but was unaltered by isoproterenol. The PLM-mediated decrease in [Na]i in WT mice could limit the isoproterenol-induced inotropic state. Indeed, the isoproterenol-induced increase in the amplitude of Ca transients was significantly smaller in the WT mice (5.2±0.4- versus 7.1±0.5-fold in PLM-KO mice). This also was the case for the sarcoplasmic reticulum Ca content, which increased by 1.27±0.09-fold in WT mice versus 1.53±0.09-fold in PLM-KO mice. The higher sarcoplasmic reticulum Ca content in PLM-KO versus WT mice was associated with an increased propensity for spontaneous Ca transients and contractions in PLM-KO mice. CONCLUSIONS - These data suggest that PLM phosphorylation and NKA stimulation are an integral part of the sympathetic fight-or-flight response, tempering the rise in [Na]i and cellular Ca loading and perhaps limiting Ca overload-induced arrhythmias.

Original languageEnglish (US)
Pages (from-to)1849-1855
Number of pages7
JournalCirculation
Volume117
Issue number14
DOIs
StatePublished - Apr 2008

Keywords

  • Arrhythmia
  • Calcium
  • Sodium

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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