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Encyclopedia of Signaling Molecules pp 1875–1883Cite as

FXYD1 (Phospholemman)

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Synonyms

FXYD protein 1; FXYD1; Phospholemman; PLM

Historical Background

Phospholemman (PLM) is a 72-amino-acid type I single-span membrane protein, belonging to the FXYD (pronounced “fix-it”) family of ion transport regulators. These smallmembrane proteins are tissue-specific regulators of the Na/K ATPase (Na/K pump or NKA). PLM is predominantly expressed in striated (cardiac and skeletal) and smooth muscle (Bogaev et al. 2001; Rembold et al. 2005). However, it is also detectable to a lesser extent in the kidney (Wetzel and Sweadner 2003), liver (Bogaev et al. 2001), cerebellum, and choroid plexus (Feschenko et al. 2003).

PLM was first identified in canine and guinea pig myocardium as a 15 kDa sarcolemmal protein and was later shown to be the principle sarcolemmal substrate for protein kinases A and C (PKA and PKC) (Presti et al. 1985a, b). At the time, the correlation between PLM phosphorylation and PKA-induced positive inotropy led Prest and colleagues to speculate that this small...

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References

  • Attali B, Latter H, Rachamim N, Garty H. A corticosteroid-induced gene expressing an “IsK-like” K+ channel activity in Xenopus oocytes. Proc Natl Acad Sci USA. 1995;92:6092–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Beguin P, Crambert G, Monnet-Tschudi F, Uldry M, Horisberger JD, Garty H, et al. FXYD7 is a brain-specific regulator of Na,K-ATPase alpha 1-beta isozymes. EMBO J. 2002;21:3264–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Beguin P, Wang X, Firsov D, Puoti A, Claeys D, Horisberger JD, et al. The gamma subunit is a specific component of the Na,K-ATPase and modulates its transport function. EMBO J. 1997;16:4250–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bell JR, Kennington E, Fuller W, Dighe K, Donoghue P, Clark JE, et al. Characterization of the phospholemman knockout mouse heart: depressed left ventricular function with increased Na-K-ATPase activity. Am J Physiol Heart Circ Physiol. 2008;294:H613–21.

    Article  PubMed  CAS  Google Scholar 

  • Bell JR, Lloyd D, Curl CL, Delbridge LM, Shattock MJ. Cell volume control in phospholemman (PLM) knockout mice: do cardiac myocytes demonstrate a regulatory volume decrease and is this influenced by deletion of PLM? Exp Physiol. 2009;94:330–43.

    Article  PubMed  CAS  Google Scholar 

  • Bibert S, Liu CC, Figtree GA, Garcia A, Hamilton EJ, Marassi FM, et al. FXYD proteins reverse inhibition of the Na+-K+ pump mediated by glutathionylation of its β1 subunit. J Biol Chem. 2011;286:18562–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bogaev RC, Jia LG, Kobayashi YM, Palmer CJ, Mounsey JP, Moorman JR, et al. Gene structure and expression of phospholemman in mouse. Gene. 2001;271:69–79.

    Article  PubMed  CAS  Google Scholar 

  • Boguslavskyi A, Pavlovic D, Aughton K, Clark JE, Howie J, Fuller W, et al. Cardiac hypertrophy in mice expressing unphosphorylatable phospholemman. Cardiovasc Res. 2014;104:72–82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bossuyt J, Despa S, Han F, Hou Z, Robia SL, Lingrel JB, et al. Isoform specificity of the Na/K-ATPase association and regulation by phospholemman. J Biol Chem. 2009;284:26749–57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bossuyt J, Despa S, Martin JL, Bers DM. Phospholemman phosphorylation alters its fluorescence resonance energy transfer with the Na/K-ATPase pump. J Biol Chem. 2006;281:32765–73.

    Article  PubMed  CAS  Google Scholar 

  • Cheung JY, Zhang XQ, Song J, Gao E, Rabinowitz JE, Chan TO, et al. Phospholemman: a novel cardiac stress protein. J Clin Transl Sci. 2010;3:189–96.

    Article  CAS  Google Scholar 

  • Crambert G, Fuzesi M, Garty H, Karlish S, Geering K. Phospholemman (FXYD1) associates with Na,K-ATPase and regulates its transport properties. Proc Natl Acad Sci USA. 2002;99:11476–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Despa S, Bossuyt J, Han F, Ginsburg KS, Jia LG, Kutchai H, et al. Phospholemman-phosphorylation mediates the β-adrenergic effects on Na/K pump function in cardiac myocytes. Circ Res. 2005;97:252–9.

    Article  PubMed  CAS  Google Scholar 

  • Despa S, Tucker AL, Bers DM. Phospholemman-mediated activation of Na/K-ATPase limits [Na]i and inotropic state during β-adrenergic stimulation in mouse ventricular myocytes. Circulation. 2008;117:1849–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • El-Armouche A, Wittkopper K, Fuller W, Howie J, Shattock MJ, Pavlovic D. Phospholemman-dependent regulation of the cardiac Na/K-ATPase activity is modulated by inhibitor-1 sensitive type-1 phosphatase. FASEB J. 2011;25:4467–75.

    Article  PubMed  CAS  Google Scholar 

  • Feschenko MS, Donnet C, Wetzel RK, Asinovski NK, Jones LR, Sweadner KJ. Phospholemman, a single-span membrane protein, is an accessory protein of Na,K-ATPase in cerebellum and choroid plexus. J Neurosci. 2003;23:2161–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fu X, Kamps MP. E2a-Pbx1 induces aberrant expression of tissue-specific and developmentally regulated genes when expressed in NIH 3 T3 fibroblasts. Mol Cell Biol. 1997;17:1503–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fuller W, Howie J, McLatchie LM, Weber RJ, Hastie CJ, Burness K, et al. FXYD1 phosphorylation in vitro and in adult rat cardiac myocytes: threonine 69 is a novel substrate for protein kinase C. Am J Physiol Cell Physiol. 2009;296:C1346–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Garty H, Karlish SJ. Role of FXYD proteins in ion transport. Annu Rev Physiol. 2006;68:431–59.

    Article  CAS  PubMed  Google Scholar 

  • Geering K. FXYD proteins: new regulators of Na-K-ATPase. Am J Physiol Renal Physiol. 2006;290:F241–50.

    Article  PubMed  CAS  Google Scholar 

  • Han F, Bossuyt J, Despa S, Tucker AL, Bers DM. Phospholemman phosphorylation mediates the protein kinase C-dependent effects on Na+/K+ pump function in cardiac myocytes. Circ Res. 2006;99:1376–83.

    Article  PubMed  CAS  Google Scholar 

  • Howie J, Tulloch LB, Shattock MJ, Fuller W. Regulation of the cardiac Na+ pump by palmitoylation of its catalytic and regulatory subunits. Biochem Soc Trans. 2013;41:95–100.

    Article  PubMed  CAS  Google Scholar 

  • Kaplan JH. Biochemistry of Na. K-ATPase Annu Rev Biochem. 2002;71:511–35.

    Article  PubMed  CAS  Google Scholar 

  • Lindzen M, Gottschalk KE, Fuzesi M, Garty H, Karlish SJ. Structural interactions between FXYD proteins and Na+,K+-ATPase: α/β/FXYD subunit stoichiometry and cross-linking. J Biol Chem. 2006;281:5947–55.

    Article  PubMed  CAS  Google Scholar 

  • Mercer RW, Biemesderfer D, Bliss Jr DP, Collins JH, Forbush B. Molecular cloning and immunological characterization of the gamma polypeptide, a small protein associated with the Na. K-ATPase J Biol Chem. 1993;121:579–86.

    CAS  Google Scholar 

  • Mirza MA, Zhang XQ, Ahlers BA, Qureshi A, Carl LL, Song J, et al. Effects of phospholemman downregulation on contractility and [Ca2+]i transients in adult rat cardiac myocytes. Am J Physiol Heart Circ Physiol. 2004;286:H1322–30.

    Article  PubMed  CAS  Google Scholar 

  • Mishra NK, Habeck M, Kirchner C, Haviv H, Peleg Y, Eisenstein M, et al. Molecular mechanisms and kinetic effects of FXYD1 and phosphomimetic mutants on purified human Na, K-ATPase. J Biol Chem. 2015;290:28746–59.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Moorman JR, Ackerman SJ, Kowdley GC, Griffin MP, Mounsey JP, Chen Z, et al. Unitary anion currents through phospholemman channel molecules. Nature. 1995;377:737–40.

    Article  PubMed  CAS  Google Scholar 

  • Moorman JR, Palmer CJ, John 3rd JE, Durieux ME, Jones LR. Phospholemman expression induces a hyperpolarization-activated chloride current in Xenopus oocytes. J Biol Chem. 1992;267:14551–4.

    PubMed  CAS  Google Scholar 

  • Morrison BW, Moorman JR, Kowdley GC, Kobayashi YM, Jones LR, Leder P. Mat-8, a novel phospholemman-like protein expressed in human breast tumors, induces a chloride conductance in Xenopus oocytes. J Biol Chem. 1995;270:2176–82.

    Article  PubMed  CAS  Google Scholar 

  • Morth JP, Pedersen BP, Toustrup-Jensen MS, Sorensen TL, Petersen J, Andersen JP, et al. Crystal structure of the sodium-potassium pump. Nature. 2007;450:1043–9.

    Article  PubMed  CAS  Google Scholar 

  • Palmer CJ, Scott BT, Jones LR. Purification and complete sequence determination of the major plasma membrane substrate for cAMP-dependent protein kinase and protein kinase C in myocardium. J Biol Chem. 1991;266:11126–30.

    PubMed  CAS  Google Scholar 

  • Pavlovic D, Fuller W, Shattock MJ. The intracellular region of FXYD1 is sufficient to regulate cardiac Na/K ATPase. FASEB J. 2007;21:1539–46.

    Article  PubMed  CAS  Google Scholar 

  • Pavlovic D, Fuller W, Shattock MJ. Novel regulation of cardiac Na pump via phospholemman. J Mol Cell Cardiol. 2013a;61:83–93.

    Article  PubMed  CAS  Google Scholar 

  • Pavlovic D, Hall AR, Kennington EJ, Aughton K, Boguslavskyi A, Fuller W, et al. Nitric oxide regulates cardiac intracellular Na+ and Ca2+ by modulating Na/K ATPase via PKCε and phospholemman-dependent mechanism. J Mol Cell Cardiol. 2013b;61:164–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pirkmajer S, Chibalin AV. Na,K-ATPase regulation in skeletal muscle. Am J Physiol Endocrinol Metab. 2016;311:E1–e31.

    Article  PubMed  Google Scholar 

  • Presti CF, Jones LR, Lindemann JP. Isoproterenol-induced phosphorylation of a 15-kilodalton sarcolemmal protein in intact myocardium. J Biol Chem. 1985a;260:3860–7.

    PubMed  CAS  Google Scholar 

  • Presti CF, Scott BT, Jones LR. Identification of an endogenous protein kinase C activity and its intrinsic 15-kilodalton substrate in purified canine cardiac sarcolemmal vesicles. J Biol Chem. 1985b;260:13879–89.

    PubMed  CAS  Google Scholar 

  • Rembold CM, Ripley ML, Meeks MK, Geddis LM, Kutchai HC, Marassi FM, et al. Serine 68 phospholemman phosphorylation during forskolin-induced swine carotid artery relaxation. J Vasc Res. 2005;42:483–91.

    Article  PubMed  CAS  Google Scholar 

  • Sweadner KJ, Rael E. The FXYD gene family of small ion transport regulators or channels: cDNA sequence, protein signature sequence, and expression. Genomics. 2000;68:41–56.

    Article  PubMed  CAS  Google Scholar 

  • Teriete P, Franzin CM, Choi J, Marassi FM. Structure of the Na,K-ATPase regulatory protein FXYD1 in micelles. Biochemistry. 2007;46:6774–83.

    Article  PubMed  CAS  Google Scholar 

  • Therien AG, Blostein R. Mechanisms of sodium pump regulation. Am J Physiol Cell Physiol. 2000;279:C541–66.

    Article  CAS  PubMed  Google Scholar 

  • Tulloch LB, Howie J, Wypijewski KJ, Wilson CR, Bernard WG, Shattock MJ, et al. The inhibitory effect of phospholemman on the sodium pump requires its palmitoylation. J Biol Chem. 2011;286:36020–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang X, Gao G, Guo K, Yarotskyy V, Huang C, Elmslie KS, et al. Phospholemman modulates the gating of cardiac L-type calcium channels. Biophys J. 2010;98:1149–59.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wetzel RK, Sweadner KJ. Phospholemman expression in extraglomerular mesangium and afferent arteriole of the juxtaglomerular apparatus. Am J Physiol Renal Physiol. 2003;285:F121–9.

    Article  PubMed  CAS  Google Scholar 

  • Yamaguchi F, Yamaguchi K, Tai Y, Sugimoto K, Tokuda M. Molecular cloning and characterization of a novel phospholemman-like protein from rat hippocampus. Brain Res Mol Brain Res. 2001;86:189–92.

    Article  PubMed  CAS  Google Scholar 

  • Zhang XQ, Qureshi A, Song J, Carl LL, Tian Q, Stahl RC, et al. Phospholemman modulates Na+/Ca2+ exchange in adult rat cardiac myocytes. Am J Physiol Heart Circ Physiol. 2003;284:H225–33.

    Article  PubMed  CAS  Google Scholar 

  • Zhang XQ, Wang J, Song J, Rabinowitz J, Chen X, Houser SR, et al. Regulation of L-type calcium channel by phospholemman in cardiac myocytes. J Mol Cell Cardiol. 2015;84:104–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Authors and Affiliations

  1. British Heart Foundation Centre of Research Excellence, Cardiovascular Division, King’s College London, The Rayne Institute, St Thomas’ Hospital, London, UK

    Kyung Chan Park & Michael J. Shattock

  2. Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK

    Davor Pavlovic

Authors
  1. Kyung Chan Park
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  2. Davor Pavlovic
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  3. Michael J. Shattock
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Correspondence to Michael J. Shattock .

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Editors and Affiliations

  1. Department of Molecular Science and Technology, Ajou University, Suwon, Korea

    Sangdun Choi

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Park, K.C., Pavlovic, D., Shattock, M.J. (2018). FXYD1 (Phospholemman). In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham. https://doi.org/10.1007/978-3-319-67199-4_101757

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