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

Research output: Contribution to journalArticle

  • External authors:
  • Nora Linscheid
  • Pi Camilla Poulsen
  • Shanzhuo Zhang
  • Maren Schrölkamp
  • Kristoffer Lihme Egerod
  • Jonatan James Thompson
  • Henggui Zhang
  • Tune H. Pers
  • Jesper Velgaard Olsen
  • Alicia Lundby

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. By high-resolution mass spectrometry, we 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 reveals 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.

Bibliographical metadata

Original languageEnglish
JournalNature Communications
Volume10
Issue number1
Early online date28 Jun 2019
DOIs
Publication statusPublished - 2019