Journal
PROTEIN & CELL
Volume 12, Issue 7, Pages 545-556Publisher
OXFORD UNIV PRESS
DOI: 10.1007/s13238-020-00820-9
Keywords
sinoatrial node; pacemaker cell; glutamatergic neuron; single-cell RNA-seq; electrophysiology
Categories
Funding
- National Key Research and Development Plan [2019YFA0801501, 2017YFC1001300, 2016YFC1000208]
- National Natural Science Foundation of China [82088101, 81930013, 81530017, 81770397, 81771651, 81770267, 82070271, 81900297, 82070338]
- Key Disciplines Group Construction Project of Pudong Health Bureau of Shanghai [PWZxq2017-05]
- Top-level Clinical Discipline Project of Shanghai Pudong District [PWYgf2018-02]
- Programfor the Research Unit of Origin and Regulation of Heart Rhythm, Chinese Academy of Medical Sciences [2019RU045]
- Innovative research team of highlevel local universities in Shanghai
- Education Commission of Shanghai Municipality [ZDSYS14005]
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Researchers found that activation of the heart originates in the sinoatrial node, where pacemaker cells exhibit properties similar to glutamatergic neurons. By comparing transcriptomes, similarities between pacemaker cells and cortical neurons suggest that the glutamatergic neurotransmitter system may play a role in regulating heart rhythms.
Activation of the heart normally begins in the sinoatrial node (SAN). Electrical impulses spontaneously released by SAN pacemaker cells (SANPCs) trigger the contraction of the heart. However, the cellular nature of SANPCs remains controversial. Here, we report that SANPCs exhibit glutamatergic neuron-like properties. By comparing the single-cell transcriptome of SANPCs with that of cells from primary visual cortex in mouse, we found that SANPCs co-clustered with cortical neurons. Tissue and cellular imaging confirmed that SANPCs contained key elements of glutamatergic neurotransmitter system, expressing genes encoding glutamate synthesis pathway (Gls), ionotropic and metabotropic glutamate receptors (Grina, Gria3, Grm1 and Grm5), and glutamate transporters (Slc17a7). SANPCs highly expressed cell markers of glutamatergic neurons (Snap25 and Slc17a7), whereas Gad1, a marker of GABAergic neurons, was negative. Functional studies revealed that inhibition of glutamate receptors or transporters reduced spontaneous pacing frequency of isolated SAN tissues and spontaneous Ca2+ transients frequency in single SANPC. Collectively, our work suggests that SANPCs share dominant biological properties with glutamatergic neurons, and the glutamatergic neurotransmitter system may act as an intrinsic regulation module of heart rhythm, which provides a potential intervention target for pacemaker cell-associated arrhythmias.
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