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.
%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
}