Zhigang Xue
Jinfeng Xue
Duanyang Xie
Ke Xiong
Huixing Zhou
Fulei Zhang
Xuling Su
Guanghua Wang
Qicheng Zou
Yi Liu
Jian Yang
Honghui Ma
Luying Peng
Chunyu Zeng
Gang Li
Li Wang
Yi-Han Chen
1 Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China;
2 Key Laboratory of Arrhythmias of the Ministry of Education of China, Tongji University School of Medicine, Shanghai 200120, China;
3 Institute of Medical Genetics, Tongji University, Shanghai 200092, China;
4 Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200092, China;
5 Reproductive Medicine Center, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China;
6 Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China;
7 Department of Cardiology, Daping Hospital, Chongqing 400042, China;
8 Department of Neurology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China;
9 State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
Funds: 81770267 and 82070271, to D.L.
This work was funded by the Grants from the National Key Research and Development Plan (2019YFA0801501, to Y.-H.C.
2017YFC1001300, 2016YFC1000208, to Z.X.), Programs of National Natural Science Foundation of China (82088101, 81930013, 81530017 and 81770397, to Y.-H.C.
81900297 and 82070338, to D.X.), Key Disciplines Group Construction Project of Pudong Health Bureau of Shanghai (PWZxq2017-05), Top-level Clinical Discipline Project of Shanghai Pudong District (PWYgf2018-02), Program for 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 and a key laboratory program of the Education Commission of Shanghai Municipality (ZDSYS14005). Y.- H.C. is a Fellow at the Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University.
81771651, to Z.X.
Received Date: 2020-11-05
Rev Recd Date:2020-12-03
Publish Date:2021-07-08
Abstract
Abstract
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.Keywords: sinoatrial node,
pacemaker cell,
glutamatergic neuron,
single-cell RNA-seq,
electrophysiology
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