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) |
|---|---|
| Pages (from-to) | 1849-1855 |
| Number of pages | 7 |
| Journal | Circulation |
| Volume | 117 |
| Issue number | 14 |
| DOIs | |
| State | Published - Apr 2008 |
Fingerprint
Keywords
- Arrhythmia
- Calcium
- Sodium
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine
Cite this
Phospholemman-mediated activation of Na/K-ATPase limits [Na]i and inotropic state during β-adrenergic stimulation in mouse ventricular myocytes. / Despa, Sanda; Tucker, Amy L.; Bers, Donald M.
In: Circulation, Vol. 117, No. 14, 04.2008, p. 1849-1855.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Phospholemman-mediated activation of Na/K-ATPase limits [Na]i and inotropic state during β-adrenergic stimulation in mouse ventricular myocytes
AU - Despa, Sanda
AU - Tucker, Amy L.
AU - Bers, Donald M
PY - 2008/4
Y1 - 2008/4
N2 - 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.
AB - 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.
KW - Arrhythmia
KW - Calcium
KW - Sodium
UR - http://www.scopus.com/inward/record.url?scp=41949138012&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=41949138012&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.107.754051
DO - 10.1161/CIRCULATIONAHA.107.754051
M3 - Article
VL - 117
SP - 1849
EP - 1855
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 14
ER -