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

Authors:	Sanda Despa, Amy L Tucker, Donald M Bers
Language:	Eng.
Date:	08-04-2008
Journal:	Circulation (1524-4539)
Release:	Circulation. 2008 Apr;117(14):1849-55
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 beta-adrenergic-induced NKA stimulation. METHODS AND RESULTS: Here, we tested whether PLM phosphorylation during beta-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 beta-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.
Copyright:	Circulation Department of Physiology, Loyola University Chicago, Maywood, Ill, USA.
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Terms:	Adrenergic beta-Agonists, Animals, Animals, Congenic, Arrhythmias, Cardiac, Calcium Signaling, Cardiac Pacing, Artificial, Cardiotonic Agents, Enzyme Activation, Heart Ventricles, Ion Channel Gating, Isoproterenol, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocytes, Cardiac, Phosphoproteins, Phosphorylation, Protein Processing, Post-Translational, Receptors, Adrenergic, beta, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Sodium