%0 Journal Article %1 Desp_2008_1849 %A Despa, Sanda %A Tucker, Amy L %A Bers, Donald M %D 2008 %J Circulation %K ATPases, Activation, Adrenergic Adrenergic, Agents, Animals, Animals; Arrhythmias, Artificial; C57BL; Calcium Calcium-Transporting Cardiac Cardiac, Cardiotonic Channel Congenic; Enzyme Gating, Heart Inbred Ion Isoproterenol, Knockout; Membrane Mice, Mice; Myocytes, Pacing, Phosphoproteins, Phosphorylation; Post-Translational; Processing, Protein Proteins, Receptors, Reticulum Sarcoplasmic Signaling; Sodium, Ventricles; beta, beta-Agonists, chemically drug effects/metabolism; effects; induced/physiopathology; metabolism physiology; toxicity; %N 14 %P 1849--1855 %R 10.1161/CIRCULATIONAHA.107.754051 %T Phospholemman-mediated activation of Na/K-ATPase limits Nai and inotropic state during beta-adrenergic stimulation in mouse ventricular myocytes. %U http://dx.doi.org/10.1161/CIRCULATIONAHA.107.754051 %V 117 %X 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.

@article{Desp_2008_1849, 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.}, added-at = {2009-06-03T11:20:58.000+0200}, author = {Despa, Sanda and Tucker, Amy L and Bers, Donald M}, biburl = {https://www.bibsonomy.org/bibtex/2bce9974df57b90f1a60fb5a532261ae6/hake}, description = {The whole bibliography file I use.}, doi = {10.1161/CIRCULATIONAHA.107.754051}, file = {Desp_2008_1849.pdf:Desp_2008_1849.pdf:PDF}, institution = {Department of Physiology, Loyola University Chicago, Maywood, Ill, USA.}, interhash = {a07beef50b567fea300c4ce742031d8e}, intrahash = {bce9974df57b90f1a60fb5a532261ae6}, journal = {Circulation}, keywords = {ATPases, Activation, Adrenergic Adrenergic, Agents, Animals, Animals; Arrhythmias, Artificial; C57BL; Calcium Calcium-Transporting Cardiac Cardiac, Cardiotonic Channel Congenic; Enzyme Gating, Heart Inbred Ion Isoproterenol, Knockout; Membrane Mice, Mice; Myocytes, Pacing, Phosphoproteins, Phosphorylation; Post-Translational; Processing, Protein Proteins, Receptors, Reticulum Sarcoplasmic Signaling; Sodium, Ventricles; beta, beta-Agonists, chemically drug effects/metabolism; effects; induced/physiopathology; metabolism physiology; toxicity;}, month = Apr, number = 14, pages = {1849--1855}, pdf = {Desp_2008_1849.pdf}, pii = {CIRCULATIONAHA.107.754051}, pmid = {18362230}, timestamp = {2009-06-03T11:21:10.000+0200}, title = {Phospholemman-mediated activation of Na/K-ATPase limits [Na]i and inotropic state during beta-adrenergic stimulation in mouse ventricular myocytes.}, url = {http://dx.doi.org/10.1161/CIRCULATIONAHA.107.754051}, volume = 117, year = 2008 }