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

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Dokumenter

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

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.
OriginalsprogEngelsk
Artikelnummer2889
TidsskriftNature Communications
Vol/bind10
Antal sider19
ISSN2041-1723
DOI
StatusUdgivet - 2019

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