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  • Review Article
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Calcium

Phospholamban: a crucial regulator of cardiac contractility

Key Points

  • The regulation of intracellular Ca2+ is key to cardiac function. A large fraction of Ca2+ is released from the sarcoplasmic reticulum (SR) to initiate contraction and is pumped back into the SR to initiate relaxation by the sarco(endo)plasmic reticulum Ca2+-ATPase SERCA2a, the activity of which is regulated by phospholamban (PLN).

  • The inhibitory interaction between SERCA2a and PLN, as deduced from biochemical studies and structural modelling, involves sites of interaction that are located in the transmembrane and cytosolic domains of the two proteins. The interactions are disrupted by Ca2+ binding to SERCA2a, which brings about vast conformational changes that force PLN out of its transmembrane binding site, or by phosphorylation of PLN. Here the structural basis for disruption of the inhibited complex is less clear.

  • The ablation of PLN in mice prevents SERCA2a inhibition and enhances cardiac contractility by increasing the SR Ca2+ store. The ablation of PLN also reverses heart failure in some cardiomyopathic animal models, indicating the possibility of therapeutic approaches.

  • The overexpression of PLN in mouse heart depresses cardiac function and proves that only 40% of SERCA pumps are normally regulated by PLN in mouse heart.

  • The superinhibition of SERCA by specific PLN mutants impairs cardiac function and leads to cardiac remodelling and early death if the effects of the mutation cannot be reversed by β-agonists.

  • In human and animal models of heart failure, the PLN–SERCA inhibited complex increases. Interventions that diminish the PLN–SERCA complex have been beneficial in some mouse models of heart failure.

  • Specific human PLN mutations cause dilated cardiomyopathy: one mutation functions as a chronic SERCA2a inhibitor, whereas another destabilizes PLN, resulting in a PLN-null phenotype. So, for correct human cardiac function, there is a fine balance between excess inhibition of SERCA2a by PLN and no inhibition.

Abstract

Heart failure is a major cause of death and disability. Impairments in blood circulation that accompany heart failure can be traced, in part, to alterations in the activity of the sarcoplasmic reticulum Ca2+ pump that are induced by its interactions with phospholamban, a reversible inhibitor. If phospholamban becomes superinhibitory or chronically inhibitory, contractility is diminished, inducing dilated cardiomyopathy in mice and humans. In mice, phospholamban seems to encumber an otherwise healthy heart, but humans with a phospholamban-null genotype develop early-onset dilated cardiomyopathy.

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Figure 1: Interactions between cardiac signalling pathways.
Figure 2: A structural model of the sites of interaction between PLN and SERCA.
Figure 3: Regulatory features of the PLN–SERCA interaction.
Figure 4: Role of PLN–SERCA2a interactions in physiological and diseased cardiac function.
Figure 5: Differences in the regulation of Ca2+ transients between mice and humans.

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Acknowledgements

We are grateful to D. Bers, A. Gramolini, K. Haghighi, G. Inesi and C. Toyoshima for their helpful comments on this manuscript. The original studies described in this review were supported by grants to D.H.M. from the Heart and Stroke Foundation of Ontario, the Canadian Institutes for Health Research and the Canadian Genetic Diseases Network of Centres of Excellence, and to E.G.K. by grants from the National Institutes of Health (USA).

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Correspondence to David H. MacLennan.

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DATABASES

LocusLink

AKAPs

ATP2A1

ATP2A2

Ca2+/CaM kinase

CACNA1S

CASQ2

PKA

PMCAs

RYR1

RYR2

Swiss-Prot

calmodulin

calsequestrin

MKP-1

PLN

SERCA1a

SERCA2a

SLN

Glossary

CARDIAC RESERVE

The maximum percentage that the cardiac output can increase above normal — the ability of the heart to adjust rapidly to demands placed on it.

β-AGONIST

A molecule that activates β-adrenergic receptors.

β-ADRENERGIC STIMULATION

The ligand- or agonist-dependent activation of β-adrenergic receptors and subsequent signalling events.

SARCOPLASMIC RETICULUM

(SR). An organellar membrane system that encases each myofibril within a muscle cell. Its essential components are a Ca2+-ATPase (Ca2+ pump), lumenal Ca2+-sequestering proteins and a Ca2+-release channel.

SARCO(ENDO)PLASMIC RETICULUM Ca2+-ATPASE

(SERCA). A pump that is located in sarcoplasmic or endoplasmic reticulum membranes that couples ATP hydrolysis to the transport of Ca2+ from cytosolic to lumenal spaces.

RYANODINE RECEPTOR

(RyR). A Ca2+-release channel that is located in the membrane of the sarcoplasmic and the endoplasmic reticulum that is regulated by protein–protein interactions with the dihydropyridine receptor and by a series of ligands, including Ca2+ itself.

DIHYDROPYRIDINE RECEPTOR

(DHPR). A slow, or L-type, voltage-dependent Ca2+-entry channel that is located in the plasma membrane. DHPRs require a membrane potential that is greater than −30 mV for activation, and they are commonly found in neurons, neuroendocrine cells and muscle cells.

PLASMA-MEMBRANE Ca2+-ATPASE

(PMCA). A plasma-membrane pump that couples ATP hydrolysis to the transport of Ca2+ from cytosolic to extracellular spaces.

Na+/Ca2+ EXCHANGER

(NCX). A plasma-membrane enzyme that exchanges three moles of Na+ for one mole of Ca2+ either inward or outward, depending on ionic gradients across the membrane.

LUSITROPIC

Affecting cardiac relaxation.

INOTROPIC

Affecting the force of cardiac contractions.

CARDIOMYOPATHY

A disease of the heart muscle.

VMAX

The maximal rate of enzymatic activity.

FAST-TWITCH SKELETAL MUSCLE

A rapidly contracting and relaxing muscle, such as the extensor digitorum longus, which is primarily involved in bodily movement.

SLOW-TWITCH SKELETAL MUSCLE

A slowly contracting muscle, such as the soleus, with major involvement in posture maintenance.

SOLEUS

A predominantly slow-twitch muscle in the leg.

G PROTEIN

A heterotrimeric, guanyl nucleotide-binding protein that transmits signals from ligand-activated receptors to effector molecules.

LOD SCORE

The log10 of the odds of linkage between genotype and phenotype versus non-linkage.

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MacLennan, D., Kranias, E. Phospholamban: a crucial regulator of cardiac contractility. Nat Rev Mol Cell Biol 4, 566–577 (2003). https://doi.org/10.1038/nrm1151

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