Outlining cardiac ion channel protein interactors and their signature in the human electrocardiogram

Research output: Contribution to journalJournal articleResearchpeer-review

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Outlining cardiac ion channel protein interactors and their signature in the human electrocardiogram. / Maurya, Svetlana; Mills, Robert W.; Kahnert, Konstantin; Chiang, David Y.; Bertoli, Giorgia; Lundegaard, Pia R.; Duran, Marta Perez Hernandez; Zhang, Mingliang; Rothenberg, Eli; George, Alfred L.; MacRae, Calum A.; Delmar, Mario; Lundby, Alicia.

In: Nature Cardiovascular Research, Vol. 2, No. 7, 2023, p. 673-692.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Maurya, S, Mills, RW, Kahnert, K, Chiang, DY, Bertoli, G, Lundegaard, PR, Duran, MPH, Zhang, M, Rothenberg, E, George, AL, MacRae, CA, Delmar, M & Lundby, A 2023, 'Outlining cardiac ion channel protein interactors and their signature in the human electrocardiogram', Nature Cardiovascular Research, vol. 2, no. 7, pp. 673-692. https://doi.org/10.1038/s44161-023-00294-y

APA

Maurya, S., Mills, R. W., Kahnert, K., Chiang, D. Y., Bertoli, G., Lundegaard, P. R., Duran, M. P. H., Zhang, M., Rothenberg, E., George, A. L., MacRae, C. A., Delmar, M., & Lundby, A. (2023). Outlining cardiac ion channel protein interactors and their signature in the human electrocardiogram. Nature Cardiovascular Research, 2(7), 673-692. https://doi.org/10.1038/s44161-023-00294-y

Vancouver

Maurya S, Mills RW, Kahnert K, Chiang DY, Bertoli G, Lundegaard PR et al. Outlining cardiac ion channel protein interactors and their signature in the human electrocardiogram. Nature Cardiovascular Research. 2023;2(7):673-692. https://doi.org/10.1038/s44161-023-00294-y

Author

Maurya, Svetlana ; Mills, Robert W. ; Kahnert, Konstantin ; Chiang, David Y. ; Bertoli, Giorgia ; Lundegaard, Pia R. ; Duran, Marta Perez Hernandez ; Zhang, Mingliang ; Rothenberg, Eli ; George, Alfred L. ; MacRae, Calum A. ; Delmar, Mario ; Lundby, Alicia. / Outlining cardiac ion channel protein interactors and their signature in the human electrocardiogram. In: Nature Cardiovascular Research. 2023 ; Vol. 2, No. 7. pp. 673-692.

Bibtex

@article{3036bbf4c9b54a1ca7eeb2623cd3f449,
title = "Outlining cardiac ion channel protein interactors and their signature in the human electrocardiogram",
abstract = "Protein–protein interactions are essential for normal cellular processes and signaling events. Defining these interaction networks is therefore crucial for understanding complex cellular functions and interpretation of disease-associated gene variants. We need to build a comprehensive picture of the interactions, their affinities and interdependencies in the specific organ to decipher hitherto poorly understood signaling mechanisms through ion channels. Here we report the experimental identification of the ensemble of protein interactors for 13 types of ion channels in murine cardiac tissue. Of these, we validated the functional importance of ten interactors on cardiac electrophysiology through genetic knockouts in zebrafish, gene silencing in mice, super-resolution microscopy and patch clamp experiments. Furthermore, we establish a computational framework to reconstruct human cardiomyocyte ion channel networks from deep proteome mapping of human heart tissue and human heart single-cell gene expression data. Finally, we integrate the ion channel interactome with human population genetics data to identify proteins that influence the electrocardiogram (ECG). We demonstrate that the combined channel network is enriched for proteins influencing the ECG, with 44% of the network proteins significantly associated with an ECG phenotype. Altogether, we define interactomes of 13 major cardiac ion channels, contextualize their relevance to human electrophysiology and validate functional roles of ten interactors, including two regulators of the sodium current (epsin-2 and gelsolin). Overall, our data provide a roadmap for our understanding of the molecular machinery that regulates cardiac electrophysiology.",
author = "Svetlana Maurya and Mills, {Robert W.} and Konstantin Kahnert and Chiang, {David Y.} and Giorgia Bertoli and Lundegaard, {Pia R.} and Duran, {Marta Perez Hernandez} and Mingliang Zhang and Eli Rothenberg and George, {Alfred L.} and MacRae, {Calum A.} and Mario Delmar and Alicia Lundby",
note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
doi = "10.1038/s44161-023-00294-y",
language = "English",
volume = "2",
pages = "673--692",
journal = "Nature Cardiovascular Research",
issn = "2731-0590",
publisher = "Springer Nature [academic journals on nature.com]",
number = "7",

}

RIS

TY - JOUR

T1 - Outlining cardiac ion channel protein interactors and their signature in the human electrocardiogram

AU - Maurya, Svetlana

AU - Mills, Robert W.

AU - Kahnert, Konstantin

AU - Chiang, David Y.

AU - Bertoli, Giorgia

AU - Lundegaard, Pia R.

AU - Duran, Marta Perez Hernandez

AU - Zhang, Mingliang

AU - Rothenberg, Eli

AU - George, Alfred L.

AU - MacRae, Calum A.

AU - Delmar, Mario

AU - Lundby, Alicia

N1 - Publisher Copyright: © 2023, The Author(s).

PY - 2023

Y1 - 2023

N2 - Protein–protein interactions are essential for normal cellular processes and signaling events. Defining these interaction networks is therefore crucial for understanding complex cellular functions and interpretation of disease-associated gene variants. We need to build a comprehensive picture of the interactions, their affinities and interdependencies in the specific organ to decipher hitherto poorly understood signaling mechanisms through ion channels. Here we report the experimental identification of the ensemble of protein interactors for 13 types of ion channels in murine cardiac tissue. Of these, we validated the functional importance of ten interactors on cardiac electrophysiology through genetic knockouts in zebrafish, gene silencing in mice, super-resolution microscopy and patch clamp experiments. Furthermore, we establish a computational framework to reconstruct human cardiomyocyte ion channel networks from deep proteome mapping of human heart tissue and human heart single-cell gene expression data. Finally, we integrate the ion channel interactome with human population genetics data to identify proteins that influence the electrocardiogram (ECG). We demonstrate that the combined channel network is enriched for proteins influencing the ECG, with 44% of the network proteins significantly associated with an ECG phenotype. Altogether, we define interactomes of 13 major cardiac ion channels, contextualize their relevance to human electrophysiology and validate functional roles of ten interactors, including two regulators of the sodium current (epsin-2 and gelsolin). Overall, our data provide a roadmap for our understanding of the molecular machinery that regulates cardiac electrophysiology.

AB - Protein–protein interactions are essential for normal cellular processes and signaling events. Defining these interaction networks is therefore crucial for understanding complex cellular functions and interpretation of disease-associated gene variants. We need to build a comprehensive picture of the interactions, their affinities and interdependencies in the specific organ to decipher hitherto poorly understood signaling mechanisms through ion channels. Here we report the experimental identification of the ensemble of protein interactors for 13 types of ion channels in murine cardiac tissue. Of these, we validated the functional importance of ten interactors on cardiac electrophysiology through genetic knockouts in zebrafish, gene silencing in mice, super-resolution microscopy and patch clamp experiments. Furthermore, we establish a computational framework to reconstruct human cardiomyocyte ion channel networks from deep proteome mapping of human heart tissue and human heart single-cell gene expression data. Finally, we integrate the ion channel interactome with human population genetics data to identify proteins that influence the electrocardiogram (ECG). We demonstrate that the combined channel network is enriched for proteins influencing the ECG, with 44% of the network proteins significantly associated with an ECG phenotype. Altogether, we define interactomes of 13 major cardiac ion channels, contextualize their relevance to human electrophysiology and validate functional roles of ten interactors, including two regulators of the sodium current (epsin-2 and gelsolin). Overall, our data provide a roadmap for our understanding of the molecular machinery that regulates cardiac electrophysiology.

U2 - 10.1038/s44161-023-00294-y

DO - 10.1038/s44161-023-00294-y

M3 - Journal article

AN - SCOPUS:85164737756

VL - 2

SP - 673

EP - 692

JO - Nature Cardiovascular Research

JF - Nature Cardiovascular Research

SN - 2731-0590

IS - 7

ER -

ID: 361848074