Ischemia‐induced phosphorylation of phospholemman directly activates rat cardiac Na/K ATPase

  title={Ischemia‐induced phosphorylation of phospholemman directly activates rat cardiac Na/K ATPase},
  author={William Fuller and Philip Eaton and James R Bell and Michael J. Shattock},
  journal={The FASEB Journal},
Regulation of the Na/K ATPase by protein kinases is model‐specific. We have observed a profound activation of the sarcolemmal Na/K ATPase during cardiac ischemia, which is masked by an inhibitor of the enzyme in the cytosol. The aim of these studies was to characterize the pathways involved in this activation in the Langendorff‐perfused rat heart. Na/K ATPase activity was determined by measuring ouabain‐sensitive phosphate generation by cardiac homogenates at 37°C. In isolated sarcolemma… 

Serine 68 phosphorylation of phospholemman: acute isoform-specific activation of cardiac Na/K ATPase.

Induced overexpression of phospholemman S68E mutant improves cardiac contractility and mortality after ischemia-reperfusion.

It is proposed that phosphorylated PLM may be a novel therapeutic target in ischemic heart disease and induced mice had similar survival as wild-type and noninduced mice.

Phospholemman-Phosphorylation Mediates the β-Adrenergic Effects on Na/K Pump Function in Cardiac Myocytes

It is concluded that PLM modulates the NKA function in a manner similar to the way phospholamban affects the related SR Ca-ATPase (inhibition of transport substrate affinity, that is relieved by phosphorylation).

Phosphorylation of Phospholemman (FXYD1) by Protein Kinases A and C Modulates Distinct Na,K-ATPase Isozymes*

Results indicate thatprotein kinase A phosphorylation of phospholemman has similar functional effects on Na,K-ATPase α1/β and α2/β isozymes and increases their apparent Na+ affinity, whereas protein kinase C modulates the transport activity of Na, K-ATpase α 2/β but not of α1/.

Expression and Phosphorylation of the Na-Pump Regulatory Subunit Phospholemman in Heart Failure

Reduced Na/K-ATPase expression in HF may be functionally offset by lower inhibition by PLM (because of reduced PLM expression and higher PLM phosphorylation), which is consistent with a role for PLM analogous to that of phospholamban for SR Ca-atPase (SERCA).

The intracellular region of FXYD1 is sufficient to regulate cardiac Na/K ATPase

  • D. PavlovicW. FullerM. Shattock
  • Biology, Chemistry
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 2007
It is concluded that unphosphorylated FXYD1 inhibits Na/K ATPase, whereas S68 phosphorylatedFXYD1 stimulates Na/k ATPase to a level above that seen in the absence of FXYD 1.

Phospholemman Inhibition of the Cardiac Na+/Ca2+ Exchanger

PLM, when phosphorylated at serine 68, inhibits Na+/Ca2+ exchange in the heart when co-expressed with NCX1, and mutating serine68 to glutamic acid resulted in additional suppression of INaCa as compared with wild-type PLM.

Phospholemman‐dependent regulation of the cardiac Na/K‐ATPase activity is modulated by inhibitor‐1 sensitive type‐1 phosphatase

This work provides the first physiological and biochemical evidence that PLM phosphorylation and cardiac Na/K‐ATPase activity are negatively regulated by PP‐1 and that this regulatory mechanism could be counteracted by I‐1.

Review Article: Phospholemman: A Novel Cardiac Stress Protein

The unique role of PLM in regulation of Na+‐K+‐ATPase, Na+/Ca2+ exchanger, and potentially L‐type Ca2+ channel in the heart, together with the changes in its expression and phosphorylation in heart failure, make PLM a rational and novel target for development of drugs in the armamentarium against heart failure.

Regulation of Cardiac Na+/Ca2+ Exchanger by Phospholemman

It is concluded that PLM regulates cardiac contractility by modulating the activities of NCX and Na+‐K+‐ATPase.



Phosphorylation of cardiac Na+-K+ ATPase by Ca2+/calmodulin dependent protein kinase.

Results suggest that phosphorylation of the alpha-subunit of Na+-K+ ATPase by an endogenous CaM kinase may lead to an inhibition of its catalytic activity.

Protein kinase C translocation and PKC-dependent protein phosphorylation during myocardial ischemia.

  • C. AlbertD. Ford
  • Biology, Chemistry
    American journal of physiology. Heart and circulatory physiology
  • 1999
The present findings are the first to demonstrate that specific PKC isozymes are translocated to particulate fractions in the isChemic and the reperfused ischemic rat heart, resulting in the phosphorylation of specific particulate-associated proteins.

Phosphorylation of Na,K-ATPase by Protein Kinase C at Ser18 Occurs in Intact Cells but Does Not Result in Direct Inhibition of ATP Hydrolysis*

A sensitive, antibody-based assay for detection of the level of phosphorylation of the α1-isoform of rat Na,K-ATPase at the serine residue that is most readily phosphorylated by protein kinase C (PKC) in vitro, Ser18 is developed.

Isoproterenol-induced phosphorylation of a 15-kilodalton sarcolemmal protein in intact myocardium.

Results demonstrate phosphorylation of a sarcolemmal protein, distinct from phospholamban, in response to beta-adrenergic stimulation of the heart, which may play a role in mediating the effects of beta- adrenergic agonists on cardiac contractile force.

Interaction of Protein Kinase C and cAMP-dependent Pathways in the Phosphorylation of the Na,K-ATPase*

The hypothesis that there is cross-talk between the protein kinase C (PKC) andprotein kinase A (PKA) pathways in the regulation of the Na,K-ATPase is tested and it is evidently mediated by events occurring at the cellular level.

Phosphorylation of the alpha-subunits of the Na+/K+-ATPase from mammalian kidneys and Xenopus oocytes by cGMP-dependent protein kinase results in stimulation of ATPase activity.

PKG plays regulatory role in active transmembraneous transport of Na+ and K+ via phosphorylation of the catalytic subunit of the Na+/K+-ATPase.

Modulation of Na,K-ATPase by Associated Small Transmembrane Regulatory Proteins and by Lipids

A regulatory mechanism is described in which association/dissociation of PLMS with the Na,K-ATPase is governed by its phosphorylation by protein kinases.

Phospholemman (FXYD1) associates with Na,K-ATPase and regulates its transport properties

It is demonstrated that phospholemman (PLM) (FXYD1), so far considered to be a heart- and muscle-specific channel or channel-regulating protein, associates specifically and stably with six different α-β isozymes of NKA after coexpression in Xenopus oocytes, and with α1–β, and less efficiently with α2–β iszymes, in native cardiac and skeletal muscles.

[Ca2+]i determines the effects of protein kinases A and C on activity of rat renal Na+,K+‐ATPase

It is concluded that effect of PKA/PKC on NKA activity is dependent on [Ca2+]i, and this Ca2+ dependence may provide an explanation for the diversity of responses of NKA to activation of either PKA or PKC.