A novel human R25C-phospholamban mutation is associated with super-inhibition of calcium cycling and ventricular arrhythmia

Liu, Guansheng; Morales, Ana; Vafiadaki, Elizabeth; Lam, Chi Keung; Cai, Wenfeng; Haghighi, Kobra; Adly, George; Hershberger, Ray E.; Kranias, Evangelia G.

doi:10.1093/cvr/cvv127

Cited by 74 publications

(65 citation statements)

References 45 publications

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“…Originally identified by WES of a DCM family with significant ventricular arrhythmias requiring ICD placement, this mutation caused super-inhibition of SERCA2a when virally over-expressed in adult cardiomyocytes. 218 This resulted in decreased SR Ca 2+ content and reduced Ca 2+ transient amplitude which is consistent with the loss of systolic function observed in DCM. Further, increased Ca 2+ spark frequency and spontaneous Ca 2+ waves were seen, suggesting DAD-type arrhythmia susceptibility.…”

Section: Arrhythmias Caused By Heritable Defects In Calcium-handling supporting

confidence: 77%

“…Further, increased Ca 2+ spark frequency and spontaneous Ca 2+ waves were seen, suggesting DAD-type arrhythmia susceptibility. 218 While the mechanism of increased SR Ca 2+ leak is unknown, it is possible that CaMKII activity is increased in the setting of elevated myocyte Ca 2+ levels. Additional studies specifically exploring the interaction between SERCA2a function and RyR2 gating are needed to clarify this relationship.…”

Section: Arrhythmias Caused By Heritable Defects In Calcium-handling mentioning

confidence: 99%

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Calcium Signaling and Cardiac Arrhythmias

Landstrom

Dobrev

Wehrens

2017

Circulation Research

410

331

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There has been significant progress in our understanding of the molecular mechanisms by which calcium (Ca2+) ions mediate various types of cardiac arrhythmias. A growing list of inherited gene defects can cause potentially lethal cardiac arrhythmia syndromes, including catecholaminergic polymorphic ventricular tachycardia, congenital long QT syndrome, and hypertrophic cardiomyopathy. In addition, acquired deficits of multiple Ca2+-handling proteins can contribute to the pathogenesis of arrhythmias in patients with various types of heart disease. In this review article, we will first review the key role of Ca2+ in normal cardiac function - in particular, excitation-contraction coupling and normal electrical rhythms. The functional involvement of Ca2+ in distinct arrhythmia mechanisms will be discussed, followed by various inherited arrhythmia syndromes caused by mutations in Ca2+-handling proteins. Finally, we will discuss how changes in the expression of regulation of Ca2+ channels and transporters can cause acquired arrhythmias, and how these mechanisms might be targeted for therapeutic purposes.

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Section: Arrhythmias Caused By Heritable Defects In Calcium-handling supporting

confidence: 77%

Section: Arrhythmias Caused By Heritable Defects In Calcium-handling mentioning

confidence: 99%

Calcium Signaling and Cardiac Arrhythmias

Landstrom

Dobrev

Wehrens

2017

Circulation Research

410

331

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“…More recently, Kranias and co-workers identified another mutation of PLN at Arginine 25 (PLN R25C ). As for the R9C, the arginine 25 was mutated into a cysteine with cardiotoxic effects associated with SERCA super-inhibition and arrhythmia[23]. To date, the molecular mechanisms for dysregulation of Ca 2+ transport by these mutants are still unclear.…”

Section: Introductionmentioning

confidence: 99%

Effects of the Arg9Cys and Arg25Cys mutations on phospholamban's conformational equilibrium in membrane bilayers

Nelson

Gopinath

et al. 2018

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Approximately, 70% of the Ca ion transport into the sarcoplasmic reticulum is catalyzed by the sarcoplasmic reticulum Ca-ATPase (SERCA), whose activity is endogenously regulated by phospholamban (PLN). PLN comprises a TM inhibitory region and a cytoplasmic regulatory region that harbors a consensus sequence for cAMP-dependent protein kinase (PKA). The inhibitory region binds the ATPase, reducing its apparent Ca binding affinity. β-adrenergic stimulation activates PKA, which phosphorylates PLN at Ser 16, reversing its inhibitory function. Mutations and post-translational modifications of PLN may lead to dilated cardiomyopathy (DCM) and heart failure. PLN's cytoplasmic region interconverts between a membrane-associated T state and a membrane-detached R state. The importance of these structural transitions on SERCA regulation is emerging, but the effects of natural occurring mutations and their relevance to the progression of heart disease are unclear. Here we use solid-state NMR spectroscopy to investigate the structural dynamics of two lethal PLN mutations, R9C and R25C, which lead to DCM. We found that the R25C mutant enhances the dynamics of PLN and shifts the conformational equilibrium toward the R state confirmation, whereas the R9C mutant drives the amphipathic cytoplasmic domain toward the membrane-associate state, enriching the T state population. The changes in membrane interactions caused by these mutations may explain the aberrant regulation of SERCA.

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“…The phenotype with PLN mutations is variable. Early onset DCM with lethal ventricular arrhythmias was described 98, 99 . Similarly, individuals from the Netherlands with the R14del founder mutation have a severe phenotype 100 .…”

Section: Dcm Geneticsmentioning

confidence: 99%

Dilated Cardiomyopathy

McNally

Mestroni

2017

Circulation Research

566

303

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Nonischemic dilated cardiomyopathy often has a genetic etiology. Because of the large number of genes and alleles attributed to dilated cardiomyopathy, comprehensive genetic testing encompasses ever-increasing gene panels. Genetic diagnosis can help predict prognosis, especially with regard to arrhythmia risk for certain subtypes. Moreover, cascade genetic testing in family members can identify those who are at-risk or with early stage disease, offering the opportunity for early intervention. This review will address diagnosis and management of dilated cardiomyopathy, including the role of genetic evaluation. We will also overview distinct genetic pathways linked to dilated cardiomyopathy and their pathogenetic mechanisms. Historically, cardiac morphology has been used to classify cardiomyopathy subtypes. Determining genetic variants is emerging as an additional adjunct to help further refine subtypes of dilated cardiomyopathy, especially where arrhythmia risk is increased, and ultimately contribute to clinical management.

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A novel human R25C-phospholamban mutation is associated with super-inhibition of calcium cycling and ventricular arrhythmia

Cited by 74 publications

References 45 publications

Calcium Signaling and Cardiac Arrhythmias

Calcium Signaling and Cardiac Arrhythmias

Effects of the Arg9Cys and Arg25Cys mutations on phospholamban's conformational equilibrium in membrane bilayers

Dilated Cardiomyopathy

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