TY - JOUR
T1 - Quantitative proteomics and single-nucleus transcriptomics of the sinus node elucidates the foundation of cardiac pacemaking
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
Y1 - 2019
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.
U2 - 10.1038/s41467-019-10709-9
DO - 10.1038/s41467-019-10709-9
M3 - Journal article
C2 - 31253831
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 2889
ER -