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

Nora Linscheid, Sunil Jit R. J. Logantha, Pi Camilla Poulsen, Shanzhuo Zhang, Maren Schrölkamp, Kristoffer Lihme Egerod, Jonatan James Thompson, Ashraf Kitmitto, Gina Galli, Martin J. Humphries, Henggui Zhang, Tune H. Pers, Jesper Velgaard Olsen, Mark Boyett () and Alicia Lundby ()
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Nora Linscheid: University of Copenhagen
Sunil Jit R. J. Logantha: University of Manchester
Pi Camilla Poulsen: University of Copenhagen
Shanzhuo Zhang: Harbin Institute of Technology
Maren Schrölkamp: University of Copenhagen
Kristoffer Lihme Egerod: University of Copenhagen
Jonatan James Thompson: University of Copenhagen
Ashraf Kitmitto: University of Manchester
Gina Galli: University of Manchester
Martin J. Humphries: University of Manchester
Henggui Zhang: University of Manchester
Tune H. Pers: University of Copenhagen
Jesper Velgaard Olsen: University of Copenhagen
Mark Boyett: University of Manchester
Alicia Lundby: University of Copenhagen

Nature Communications, 2019, vol. 10, issue 1, 1-19

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10709-9

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