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Coordinated Regulation of Cardiac Na+/Ca2+ Exchanger and Na+-K+-ATPase by Phospholemman (FXYD1)

  • Joseph Y. CheungEmail author
  • Xue-Qian Zhang
  • Jianliang Song
  • Erhe Gao
  • Tung O. Chan
  • Joseph E. Rabinowitz
  • Walter J. Koch
  • Arthur M. Feldman
  • JuFang Wang
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 961)

Abstract

Phospholemman (PLM) is the founding member of the FXYD family of regulators of ion transport. PLM is a 72-amino acid protein consisting of the signature PFXYD motif in the extracellular N terminus, a single transmembrane (TM) domain, and a C-terminal cytoplasmic tail containing three phosphorylation sites. In the heart, PLM co-localizes and co-immunoprecipitates with Na+-K+-ATPase, Na+/Ca2+ exchanger, and L-type Ca2+ channel. The TM domain of PLM interacts with TM9 of the α-subunit of Na+-K+-ATPase, while its cytoplasmic tail interacts with two small regions (spanning residues 248–252 and 300–304) of the proximal intracellular loop of Na+/Ca2+ exchanger. Under stress, catecholamine stimulation phosphorylates PLM at serine68, resulting in relief of inhibition of Na+-K+-ATPase by decreasing Km for Na+ and increasing Vmax, and simultaneous inhibition of Na+/Ca2+ exchanger. Enhanced Na+-K+-ATPase activity lowers intracellular Na+, thereby minimizing Ca2+ overload and risks of arrhythmias. Inhibition of Na+/Ca2+ exchanger reduces Ca2+ efflux, thereby preserving contractility. Thus, the coordinated actions of PLM during stress serve to minimize arrhythmogenesis and maintain inotropy. In acute cardiac ischemia and chronic heart failure, either expression or phosphorylation of PLM or both are altered. PLM regulates important ion transporters in the heart and offers a tempting target for development of drugs to treat heart failure.

Keywords

FXYD proteins Ion transport Cardiac excitation-contraction coupling Inotropy Arrhythmias Catecholamines Stress protein Intracellular Na+ and Ca2+ 

Notes

Acknowledgments

This work was supported in part by National Institutes of Health grants RO1-HL58672 and RO1-HL74854 (JYC); RO1-HL91096 (JER); RO1-HL56205, RO1-HL-61690, RO1-HL85503, PO1-HL-75443, and PO1-HL-91799 (WJK); and PO1-HL-91799 (AMF) and by American Heart Association Scientist Development grant F64702 (TOC).

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Joseph Y. Cheung
    • 1
    Email author
  • Xue-Qian Zhang
    • 1
  • Jianliang Song
    • 1
  • Erhe Gao
    • 1
  • Tung O. Chan
    • 1
  • Joseph E. Rabinowitz
    • 1
  • Walter J. Koch
    • 1
  • Arthur M. Feldman
    • 1
  • JuFang Wang
    • 1
  1. 1.Center of Translational MedicineTemple University School of MedicinePhiladelphiaUSA

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