Hypertrophy, increased ejection fraction, and reduced Na-K-ATPase activity in phospholemman-deficient mice.
Phospholemman (FXYD1), a 72-amino acid transmembrane protein abundantly expressed in the heart and skeletal muscle, is a major substrate for phosphorylation in the cardiomyocyte sarcolemma. Biochemical, cellular, and electrophysiological studies have suggested a number of possible roles for this protein, including ion channel modulator, taurine-release channel, Na(+)/Ca(2+) exchanger modulator, and Na-K-ATPase-associated subunit. We have generated a phospholemman-deficient mouse. The adult null mice exhibited increased cardiac mass, larger cardiomyocytes, and ejection fractions that were 9% higher by magnetic resonance imaging compared with wild-type animals. Notably, this occurred in the absence of hypertension. Total Na-K-ATPase activity was 50% lower in the phospholemman-deficient hearts. Expression (per unit of membrane protein) of total Na-K-ATPase was only slightly diminished, but expression of the minor alpha(2)-isoform, which has been specifically implicated in the control of contractility, was reduced by 60%. The absence of phospholemman thus results in a complex response, including a surprisingly large reduction in intrinsic Na-K-ATPase activity, changes in Na-K-ATPase isoform expression, increase in ejection fraction, and increase in cardiac mass. We hypothesize that a primary effect of phospholemman is to modulate the Na-K-ATPase and that its reduced activity initiates compensatory responses.
Jia
Li-Guo
LG
Dividsion of Cardiovascular Medicine, Box 801394 MR5, University of Virginia Health System, Charlottesville, VA 22908, USA.
Donnet
Claudia
C
Bogaev
Roberta C
RC
Blatt
Rebecca J
RJ
McKinney
Cindy E
CE
Day
Kathleen H
KH
Berr
Stuart S
SS
Jones
Larry R
LR
Moorman
J Randall
JR
Sweadner
Kathleen J
KJ
Tucker
Amy L
AL
D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D002460:Cell Line; D004789:Enzyme Activation; D007763:Lac Operon; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009206:Myocardium / Q000473:pathology; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism*; D012508:Sarcolemma / Q000201:enzymology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology; D013318:Stroke Volume / Q000502:physiology*
D008565:Membrane Proteins; D010750:Phosphoproteins; C069141:phospholemman; D000254:Sodium-Potassium-Exchanging ATPase