Quantitative proteomics and single-nucleus transcriptomics of the sinus node elucidates the foundation of cardiac pacemaking

Nora Linscheid; Sunil Jit R. J. Logantha; Camilla Poulsen; Shanzhuo Zhang; Maren Schrolkamp; Kristoffer Lihme Egerod; Jonatan James Thompson; Ashraf Kitmitto; Gina Galli; Martin J. Humphries; Henggui Zhang; Tune H. Pers; Jesper Velgaard Olsen; Mark Boyett; Alicia Lundby

doi:10.1038/s41467-019-10709-9

Quantitative proteomics and single-nucleus transcriptomics of the sinus node elucidates the foundation of cardiac pacemaking

Nora Linscheid, Sunil Jit R. J. Logantha, Camilla Poulsen, Shanzhuo Zhang, Maren Schrolkamp, Kristoffer Lihme Egerod, Jonatan James Thompson, Ashraf Kitmitto, Gina Galli, Martin J. Humphries, Henggui Zhang, Tune H. Pers, Jesper Velgaard Olsen, Mark Boyett, Alicia Lundby

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Abstract

The sinus node is a collection of highly specialised cells constituting the heart's pacemaker. The molecular underpinnings of its pacemaking abilities are debated. Using high-resolution mass spectrometry, we here quantify >7,000 proteins from sinus node and neighbouring atrial muscle. Abundances of 575 proteins differ between the two tissues. By performing single-nucleus RNA sequencing of sinus node biopsies, we attribute measured protein abundances to specific cell types. The data reveal significant differences in ion channels responsible for the membrane clock, but not in Ca2+ clock proteins, suggesting that the membrane clock underpins pacemaking. Consistently, incorporation of ion channel expression differences into a biophysically-detailed atrial action potential model result in pacemaking and a sinus node-like action potential. Combining our quantitative proteomics data with computational modeling, we estimate ion channel copy numbers for sinus node myocytes. Our findings provide detailed insights into the unique molecular make-up of the cardiac pacemaker.

Original language	English
Article number	2889
Journal	Nature Communications
Volume	10
Number of pages	19
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-019-10709-9
Publication status	Published - 1 Dec 2019

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Linscheid, N., Logantha, S. J. R. J., Poulsen, C., Zhang, S., Schrolkamp, M., Egerod, K. L., Thompson, J. J., Kitmitto, A., Galli, G., Humphries, M. J., Zhang, H., Pers, T. H., Olsen, J. V., Boyett, M., & Lundby, A. (2019). Quantitative proteomics and single-nucleus transcriptomics of the sinus node elucidates the foundation of cardiac pacemaking. Nature Communications, 10, [2889]. https://doi.org/10.1038/s41467-019-10709-9

Linscheid, N, Logantha, SJRJ, Poulsen, C, Zhang, S, Schrolkamp, M , Egerod, KL, Thompson, JJ, Kitmitto, A, Galli, G, Humphries, MJ, Zhang, H, Pers, TH , Olsen, JV, Boyett, M & Lundby, A 2019, 'Quantitative proteomics and single-nucleus transcriptomics of the sinus node elucidates the foundation of cardiac pacemaking', Nature Communications, vol. 10, 2889. https://doi.org/10.1038/s41467-019-10709-9

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title = "Quantitative proteomics and single-nucleus transcriptomics of the sinus node elucidates the foundation of cardiac pacemaking",

abstract = "The sinus node is a collection of highly specialised cells constituting the heart's pacemaker. The molecular underpinnings of its pacemaking abilities are debated. Using high-resolution mass spectrometry, we here quantify >7,000 proteins from sinus node and neighbouring atrial muscle. Abundances of 575 proteins differ between the two tissues. By performing single-nucleus RNA sequencing of sinus node biopsies, we attribute measured protein abundances to specific cell types. The data reveal significant differences in ion channels responsible for the membrane clock, but not in Ca2+ clock proteins, suggesting that the membrane clock underpins pacemaking. Consistently, incorporation of ion channel expression differences into a biophysically-detailed atrial action potential model result in pacemaking and a sinus node-like action potential. Combining our quantitative proteomics data with computational modeling, we estimate ion channel copy numbers for sinus node myocytes. Our findings provide detailed insights into the unique molecular make-up of the cardiac pacemaker.",

author = "Nora Linscheid and Logantha, {Sunil Jit R. J.} and Camilla Poulsen and Shanzhuo Zhang and Maren Schrolkamp and Egerod, {Kristoffer Lihme} and Thompson, {Jonatan James} and Ashraf Kitmitto and Gina Galli and Humphries, {Martin J.} and Henggui Zhang and Pers, {Tune H.} and Olsen, {Jesper Velgaard} and Mark Boyett and Alicia Lundby",

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AU - Linscheid, Nora

AU - Logantha, Sunil Jit R. J.

AU - Poulsen, Camilla

AU - Zhang, Shanzhuo

AU - Schrolkamp, Maren

AU - Egerod, Kristoffer Lihme

AU - Thompson, Jonatan James

AU - Kitmitto, Ashraf

AU - Galli, Gina

AU - Humphries, Martin J.

AU - Zhang, Henggui

AU - Pers, Tune H.

AU - Olsen, Jesper Velgaard

AU - Boyett, Mark

AU - Lundby, Alicia

PY - 2019/12/1

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N2 - The sinus node is a collection of highly specialised cells constituting the heart's pacemaker. The molecular underpinnings of its pacemaking abilities are debated. Using high-resolution mass spectrometry, we here quantify >7,000 proteins from sinus node and neighbouring atrial muscle. Abundances of 575 proteins differ between the two tissues. By performing single-nucleus RNA sequencing of sinus node biopsies, we attribute measured protein abundances to specific cell types. The data reveal significant differences in ion channels responsible for the membrane clock, but not in Ca2+ clock proteins, suggesting that the membrane clock underpins pacemaking. Consistently, incorporation of ion channel expression differences into a biophysically-detailed atrial action potential model result in pacemaking and a sinus node-like action potential. Combining our quantitative proteomics data with computational modeling, we estimate ion channel copy numbers for sinus node myocytes. Our findings provide detailed insights into the unique molecular make-up of the cardiac pacemaker.

AB - The sinus node is a collection of highly specialised cells constituting the heart's pacemaker. The molecular underpinnings of its pacemaking abilities are debated. Using high-resolution mass spectrometry, we here quantify >7,000 proteins from sinus node and neighbouring atrial muscle. Abundances of 575 proteins differ between the two tissues. By performing single-nucleus RNA sequencing of sinus node biopsies, we attribute measured protein abundances to specific cell types. The data reveal significant differences in ion channels responsible for the membrane clock, but not in Ca2+ clock proteins, suggesting that the membrane clock underpins pacemaking. Consistently, incorporation of ion channel expression differences into a biophysically-detailed atrial action potential model result in pacemaking and a sinus node-like action potential. Combining our quantitative proteomics data with computational modeling, we estimate ion channel copy numbers for sinus node myocytes. Our findings provide detailed insights into the unique molecular make-up of the cardiac pacemaker.

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