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Physiol. Rev. 78: 921-947, 1998;
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PHYSIOLOGICAL REVIEWS   Vol. 78 No. 4 October 1998, pp. 921-947
Copyright ©1998 The American Physiological Society

Phospholamban: Protein Structure, Mechanism of Action, and Role in Cardiac Function

HEATHER K. B. SIMMERMAN AND LARRY R. JONES

Amgen, Thousand Oaks, California; and Department of Medicine and the Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana

Simmerman, Heather K. B., and Larry R. Jones. Phospholamban: Protein Structure, Mechanism of Action, and Role in Cardiac Function. Physiol. Rev. 78: 921-947, 1998. --- A comprehensive discussion is presented of advances in understanding the structure and function of phospholamban (PLB), the principal regulator of the Ca2+-ATPase of cardiac sarcoplasmic reticulum. Extensive historical studies are reviewed to provide perspective on recent developments. Phospholamban gene structure, expression, and regulation are presented in addition to in vitro and in vivo studies of PLB protein structure and activity. Applications of breakthrough experimental technologies in identifying PLB structure-function relationships and in defining its interaction with the Ca2+-ATPase are also highlighted. The current leading viewpoint of PLB's mechanism of action emerges from a critical examination of alternative hypotheses and the most recent experimental evidence. The potential physiological relevance of PLB function in human heart failure is also covered. The interest in PLB across diverse biochemical disciplines portends its continued intense scrutiny and its potential exploitation as a therapeutic target.




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Circ. Res., September 20, 2002; 91(6): 517 - 524.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Heart Circ. Physiol.Home page
S. Huke, V. Prasad, M. L. Nieman, K. J. Nattamai, I. L. Grupp, J. N. Lorenz, and M. Periasamy
Altered dose response to beta -agonists in SERCA1a-expressing hearts ex vivo and in vivo
Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H958 - H965.
[Abstract] [Full Text] [PDF]

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 Cardiovasc ResHome page
M. T Gewaltig and G. Kojda
Vasoprotection by nitric oxide: mechanisms and therapeutic potential
Cardiovasc Res, August 1, 2002; 55(2): 250 - 260.
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L. R. Jones, R. L. Cornea, and Z. Chen
Close Proximity between Residue 30 of Phospholamban and Cysteine 318 of the Cardiac Ca2+ Pump Revealed by Intermolecular Thiol Cross-linking
J. Biol. Chem., July 26, 2002; 277(31): 28319 - 28329.
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 Proc. Natl. Acad. Sci. USAHome page
K. P. Howard, J. D. Lear, and W. F. DeGrado
Sequence determinants of the energetics of folding of a transmembrane four-helix-bundle protein
PNAS, June 25, 2002; 99(13): 8568 - 8572.
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 Mol. Cell. Biol.Home page
A. N. Carr, A. G. Schmidt, Y. Suzuki, F. del Monte, Y. Sato, C. Lanner, K. Breeden, S.-L. Jing, P. B. Allen, P. Greengard, et al.
Type 1 Phosphatase, a Negative Regulator of Cardiac Function
Mol. Cell. Biol., June 15, 2002; 22(12): 4124 - 4135.
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 J. Virol.Home page
C. Salaun, E. Gyan, P. Rodrigues, and J. M. Heard
Pit2 Assemblies at the Cell Surface Are Modulated by Extracellular Inorganic Phosphate Concentration
J. Virol., March 27, 2002; 76(9): 4304 - 4311.
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 Mol. Pharmacol.Home page
Y. Kimura and M. Inui
Reconstitution of the Cytoplasmic Interaction between Phospholamban and Ca2+-ATPase of Cardiac Sarcoplasmic Reticulum
Mol. Pharmacol., March 1, 2002; 61(3): 667 - 673.
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 Circ. Res.Home page
Y. Li, E. G. Kranias, G. A. Mignery, and D. M. Bers
Protein Kinase A Phosphorylation of the Ryanodine Receptor Does Not Affect Calcium Sparks in Mouse Ventricular Myocytes
Circ. Res., February 22, 2002; 90(3): 309 - 316.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Cell Physiol.Home page
G. C. Wellman, L. F. Santana, A. D. Bonev, and M. T. Nelson
Role of phospholamban in the modulation of arterial Ca2+ sparks and Ca2+-activated K+ channels by cAMP
Am J Physiol Cell Physiol, September 1, 2001; 281(3): C1029 - C1037.
[Abstract] [Full Text] [PDF]

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 Cardiovasc ResHome page
P. Boknik, I. Heinroth-Hoffmann, U. Kirchhefer, J. Knapp, B. Linck, H. Luss, T. Muller, W. Schmitz, O.-E. Brodde, and J. Neumann
Enhanced protein phosphorylation in hypertensive hypertrophy
Cardiovasc Res, September 1, 2001; 51(4): 717 - 728.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
M. Asahi, N. M. Green, K. Kurzydlowski, M. Tada, and D. H. MacLennan
Phospholamban domain IB forms an interaction site with the loop between transmembrane helices M6 and M7 of sarco(endo)plasmic reticulum Ca2+ ATPases
PNAS, August 28, 2001; 98(18): 10061 - 10066.
[Abstract] [Full Text] [PDF]

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 IOVSHome page
J. Rymer, S. S. Miller, and J. L. Edelman
Epinephrine-Induced Increases in [Ca2+]in and KCl-Coupled Fluid Absorption in Bovine RPE
Invest. Ophthalmol. Vis. Sci., July 1, 2001; 42(8): 1921 - 1929.
[Abstract] [Full Text] [PDF]

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M. Dittrich, J. Jurevicius, M. Georget, F. Rochais, B. K. Fleischmann, J. Hescheler, and R. Fischmeister
Local response of L-type Ca2+ current to nitric oxide in frog ventricular myocytes
J. Physiol., July 1, 2001; 534(1): 109 - 121.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Heart Circ. Physiol.Home page
M. K. Rao, A. Xu, and N. Narayanan
Glucocorticoid modulation of protein phosphorylation and sarcoplasmic reticulum function in rat myocardium
Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H325 - H333.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Heart Circ. Physiol.Home page
P. Boknik, S. Khorchidi, G. S. Bodor, S. Huke, J. Knapp, B. Linck, H. Luss, F. U. Muller, W. Schmitz, and J. Neumann
Role of protein phosphatases in regulation of cardiac inotropy and relaxation
Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H786 - H794.
[Abstract] [Full Text] [PDF]

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 IOVSHome page
R. H. Quinn, J. N. Quong, and S. S. Miller
Adrenergic Receptor Activated Ion Transport in Human Fetal Retinal Pigment Epithelium
Invest. Ophthalmol. Vis. Sci., January 1, 2001; 42(1): 255 - 264.
[Abstract] [Full Text]

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 J. Physiol.Home page
J.-M. Goaillard, P. Vincent, and R. Fischmeister
Simultaneous measurements of intracellular cAMP and L-type Ca2+ current in single frog ventricular myocytes
J. Physiol., January 1, 2001; 530(1): 79 - 91.
[Abstract] [Full Text] [PDF]

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 J. Pharmacol. Exp. Ther.Home page
J. Knapp, P. Bokník, B. Linck, H. Lüss, F. U. Müller, L. Petertönjes, W. Schmitz, and J. Neumann
Cantharidin Enhances Norepinephrine-Induced Vasoconstriction in an Endothelium-Dependent Fashion
J. Pharmacol. Exp. Ther., August 1, 2000; 294(2): 620 - 626.
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 J. Appl. Physiol.Home page
L.-Q. Zhang, X.-Q. Zhang, Y.-C. Ng, L. I. Rothblum, T. I. Musch, R. L. Moore, and J. Y. Cheung
Sprint training normalizes Ca2+ transients and SR function in postinfarction rat myocytes
J Appl Physiol, July 1, 2000; 89(1): 38 - 46.
[Abstract] [Full Text] [PDF]

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 Physiol. Rev.Home page
M. W. Berchtold, H. Brinkmeier, and M. Muntener
Calcium Ion in Skeletal Muscle: Its Crucial Role for Muscle Function, Plasticity, and Disease
Physiol Rev, July 1, 2000; 80(3): 1215 - 1265.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
E. Zvaritch, P. H. Backx, F. Jirik, Y. Kimura, S. de Leon, A. G. Schmidt, B. D. Hoit, J. W. Lester, E. G. Kranias, and D. H. MacLennan
The Transgenic Expression of Highly Inhibitory Monomeric Forms of Phospholamban in Mouse Heart Impairs Cardiac Contractility
J. Biol. Chem., May 12, 2000; 275(20): 14985 - 14991.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
M. Asahi, E. McKenna, K. Kurzydlowski, M. Tada, and D. H. MacLennan
Physical Interactions between Phospholamban and Sarco(endo)plasmic Reticulum Ca2+-ATPases Are Dissociated by Elevated Ca2+, but Not by Phospholamban Phosphorylation, Vanadate, or Thapsigargin, and Are Enhanced by ATP
J. Biol. Chem., May 12, 2000; 275(20): 15034 - 15038.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
K. Eizema, H. Fechner, K. Bezstarosti, S. Schneider-Rasp, A. van der Laarse, H. Wang, H.-P. Schultheiss, W. C. Poller, and J. M. J. Lamers
Adenovirus-Based Phospholamban Antisense Expression as a Novel Approach to Improve Cardiac Contractile Dysfunction : Comparison of a Constitutive Viral Versus an Endothelin-1-Responsive Cardiac Promoter
Circulation, May 9, 2000; 101(18): 2193 - 2199.
[Abstract] [Full Text] [PDF]

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A. G. Brittsan, A. N. Carr, A. G. Schmidt, and E. G. Kranias
Maximal Inhibition of SERCA2 Ca2+ Affinity by Phospholamban in Transgenic Hearts Overexpressing a Non-phosphorylatable Form of Phospholamban
J. Biol. Chem., April 14, 2000; 275(16): 12129 - 12135.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
J. Zhai, A. G. Schmidt, B. D. Hoit, Y. Kimura, D. H. MacLennan, and E. G. Kranias
Cardiac-specific Overexpression of a Superinhibitory Pentameric Phospholamban Mutant Enhances Inhibition of Cardiac Function in Vivo
J. Biol. Chem., March 31, 2000; 275(14): 10538 - 10544.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
A. Xu and N. Narayanan
Reversible Inhibition of the Calcium-pumping ATPase in Native Cardiac Sarcoplasmic Reticulum by a Calmodulin-binding Peptide. EVIDENCE FOR CALMODULIN-DEPENDENT REGULATION OF THE Vmax OF CALCIUM TRANSPORT
J. Biol. Chem., February 11, 2000; 275(6): 4407 - 4416.
[Abstract] [Full Text] [PDF]

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 Cardiovasc ResHome page
U Ravens and D Dobrev
Regulation of sarcoplasmic reticulum Ca2+-ATPase and phospholamban in the failing and nonfailing heart
Cardiovasc Res, January 1, 2000; 45(1): 245 - 252.
[Full Text] [PDF]

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 J. Biol. Chem.Home page
M. Ga{beta}el, T. Mollenkamp, W. Puppe, and K. Altendorf
The KdpF Subunit Is Part of the K+-translocating Kdp Complex of Escherichia coli and Is Responsible for Stabilization of the Complex in Vitro
J. Biol. Chem., December 31, 1999; 274(53): 37901 - 37907.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
M. Asahi, Y. Kimura, K. Kurzydlowski, M. Tada, and D. H. MacLennan
Transmembrane Helix M6 in Sarco(endo)plasmic Reticulum Ca2+-ATPase Forms a Functional Interaction Site with Phospholamban. EVIDENCE FOR PHYSICAL INTERACTIONS AT OTHER SITES
J. Biol. Chem., November 12, 1999; 274(46): 32855 - 32862.
[Abstract] [Full Text] [PDF]

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 Cardiovasc ResHome page
P. Boknik, C. Unkel, U. Kirchhefer, U. Kleideiter, O. Klein-Wiele, J. Knapp, B. Linck, H. Luss, F. Ulrich Muller, W. Schmitz, et al.
Regional expression of phospholamban in the human heart
Cardiovasc Res, July 1, 1999; 43(1): 67 - 76.
[Abstract] [Full Text] [PDF]

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 J. Pharmacol. Exp. Ther.Home page
J. Neumann, R. Maas, P. Bokník, L. R. Jones, N. Zimmermann, and H. Scholz
Pharmacological Characterization of Protein Phosphatase Activities in Preparations from Failing Human Hearts
J. Pharmacol. Exp. Ther., April 1, 1999; 289(1): 188 - 193.
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 J. Biol. Chem.Home page
L. G. Reddy, J. M. Autry, L. R. Jones, and D. D. Thomas
Co-reconstitution of Phospholamban Mutants with the Ca-ATPase Reveals Dependence of Inhibitory Function on Phospholamban Structure
J. Biol. Chem., March 19, 1999; 274(12): 7649 - 7655.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
D. Hagemann, M. Kuschel, T. Kuramochi, W. Zhu, H. Cheng, and R.-P. Xiao
Frequency-encoding Thr17 Phospholamban Phosphorylation Is Independent of Ser16 Phosphorylation in Cardiac Myocytes
J. Biol. Chem., July 14, 2000; 275(29): 22532 - 22536.
[Abstract] [Full Text] [PDF]


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