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 language | English (US) |
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Pages (from-to) | 1849-1855 |
Number of pages | 7 |
Journal | Circulation |
Volume | 117 |
Issue number | 14 |
DOIs | |
State | Published - Apr 2008 |
Keywords
- Arrhythmia
- Calcium
- Sodium
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine