Volume 12 Issue 7
Jul.  2021
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Dandan Liang, 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. Sinoatrial node pacemaker cells share dominant biological properties with glutamatergic neurons[J]. Protein&Cell, 2021, 12(7): 545-556. doi: 10.1007/s13238-020-00820-9
Citation: Dandan Liang, 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. Sinoatrial node pacemaker cells share dominant biological properties with glutamatergic neurons[J]. Protein&Cell, 2021, 12(7): 545-556. doi: 10.1007/s13238-020-00820-9

Sinoatrial node pacemaker cells share dominant biological properties with glutamatergic neurons

doi: 10.1007/s13238-020-00820-9

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
  • 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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  • [1]
    Baruscotti M, Bucchi A, Viscomi C, Mandelli G, Consalez G, Gnecchi-Rusconi T, Montano N, Casali KR, Micheloni S, Barbuti A et al (2011) Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4. Proc Natl Acad Sci USA 108:1705-1710
    Boyden PA, Dun W, Robinson RB (2016) Cardiac Purkinje fibers and arrhythmias; The GK Moe Award Lecture 2015. Heart Rhythm 13:1172-1181
    Bredeloux P, Findlay I, Pasqualin C, Hocini M, Bernus O, Maupoil V (2020) Selective inhibition of electrical conduction within the pulmonary veins by alpha1-adrenergic receptors activation in the rat. Sci Rep 10:5390
    Butler A, Hoffman P, Smibert P, Papalexi E, Satija R (2018) Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol 36:411-420
    Chandler NJ, Greener ID, Tellez JO, Inada S, Musa H, Molenaar P, Difrancesco D, Baruscotti M, Longhi R, Anderson RH et al (2009) Molecular architecture of the human sinus node:insights into the function of the cardiac pacemaker. Circulation 119:1562-1575
    Cingolani E, Goldhaber JI, Marban E (2018) Next-generation pacemakers:from small devices to biological pacemakers. Nat Rev Cardiol 15:139-150
    Clauss S, Bleyer C, Schuttler D, Tomsits P, Renner S, Klymiuk N, Wakili R, Massberg S, Wolf E, Kääb S (2019) Animal models of arrhythmia:classic electrophysiology to genetically modified large animals. Nat Rev Cardiol 16:457-475
    Divito CB, Underhill SM (2014) Excitatory amino acid transporters:roles in glutamatergic neurotransmission. Neurochem Int 73:172-180
    Dun W, Boyden PA (2008) The Purkinje cell; 2008 style. J Mol Cell Cardiol 45:617-624
    El Mestikawy S, Wallen-Mackenzie A, Fortin GM, Descarries L, Trudeau LE (2011) From glutamate co-release to vesicular synergy:vesicular glutamate transporters. Nat Rev Neurosci 12:204-216
    Ewy GA (2014) Sick sinus syndrome:synopsis. J Am Coll Cardiol 64:539-540
    Finlay M, Harmer SC, Tinker A (2017) The control of cardiac ventricular excitability by autonomic pathways. Pharmacol Ther 174:97-111
    Haghverdi L, Lun ATL, Morgan MD, Marioni JC (2018) Batch effects in single-cell RNA sequencing data are corrected by matching mutual nearest neighbours. Nat Biotechnol 36:421-427
    Herring N, Kalla M, Paterson DJ (2019) The autonomic nervous system and cardiac arrhythmias:current concepts and emerging therapies. Nat Rev Cardiol 16:707-726
    Kalmbach BE, Buchin A, Long B, Close J, Nandi A, Miller JA, Bakken TE, Hodge RD, Chong P, de Frates R et al (2018) h-Channels contribute to divergent intrinsic membrane properties of supragranular pyramidal neurons in human versus mouse cerebral cortex. Neuron 100:1194-1208
    Lakatta EG, Maltsev VA, Vinogradova TM (2010) A coupled SYSTEM of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart's pacemaker. Circ Res 106:659-673
    Li H, Li D, Wang YZ, Huang Z, Xu J, Yang T, Wang L, Tang Q, Cai CL, Huang H et al (2019) Nkx2-5 defines a subpopulation of pacemaker cells and is essential for the physiological function of the sinoatrial node in mice. Development 146:dev178145
    Linscheid N, Logantha S, Poulsen PC, Zhang S, Schrölkamp M, Egerod KL, Thompson JJ, Kitmitto A, Galli G, Humphries MJ et al (2019) Quantitative proteomics and single-nucleus transcriptomics of the sinus node elucidates the foundation of cardiac pacemaking. Nat Commun 10:2889
    Lolicato M, Bucchi A, Arrigoni C, Zucca S, Nardini M, Schroeder I, Simmons K, Aquila M, DiFrancesco D, Bolognesi M et al (2014) Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness. Nat Chem Biol 10:457-462
    Malik AR, Willnow TE (2019) Excitatory amino acid transporters in physiology and disorders of the central nervous system. Int J Mol Sci 20:5671
    Mangoni ME, Nargeot J (2008) Genesis and regulation of the heart automaticity. Physiol Rev 88:919-982
    Mangoni ME, Couette B, Bourinet E, Platzer J, Reimer D, Striessnig J, Nargeot J (2003) Functional role of L-type Cav1.3 Ca2+ channels in cardiac pacemaker activity. Proc Natl Acad Sci USA 100:5543-5548
    Morquette P, Verdier D, Kadala A, Féthière J, Philippe AG, Robitaille R, Kolta A (2015) An astrocyte-dependent mechanism for neuronal rhythmogenesis. Nat Neurosci 18:844-854
    Murphy C, Lazzara R (2016) Current concepts of anatomy and electrophysiology of the sinus node. J Interv Card Electrophysiol 46:9-18
    Nedergaard M, Takano T, Hansen AJ (2002) Beyond the role of glutamate as a neurotransmitter. Nat Rev Neurosci 3:748-755
    O'Leary T, Williams AH, Franci A, Marder E (2014) Cell types, network homeostasis, and pathological compensation from a biologically plausible ion channel expression model. Neuron 82:809-821
    Pulver SR, Griffith LC (2009) Spike integration and cellular memory in a rhythmic network from Na+/K+ pump current dynamics. Nat Neurosci 13:53-59
    Ritter P, Duray GZ, Steinwender C, Soejima K, Omar R, Mont L, Boersma LV, Knops RE, Chinitz L, Zhang S et al (2015) Early performance of a miniaturized leadless cardiac pacemaker:the Micra Transcatheter Pacing Study. Eur Heart J 36:2510-2519
    Rolston JD, Laxpati NG, Gutekunst CA, Potter SM, Gross RE (2010) Spontaneous and evoked high-frequency oscillations in the tetanus toxin model of epilepsy. Epilepsia 51:2289-2296
    Schenck S, Wojcik SM, Brose N, Takamori S (2009) A chloride conductance in VGLUT1 underlies maximal glutamate loading into synaptic vesicles. Nat Neurosci 12:156-162
    Shen MJ, Zipes DP (2014) Role of the autonomic nervous system in modulating cardiac arrhythmias. Circ Res 114:1004-1021
    Stieber J, Herrmann S, Feil S, Löster J, Feil R, Biel M, Hofmann F, Ludwig A (2003) The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in the embryonic heart. Proc Natl Acad Sci USA 100:15235-15240
    Tasic B, Menon V, Nguyen TN, Kim TK, Jarsky T, Yao Z, Levi B, Gray LT, Sorensen SA, Dolbeare T et al (2016) Adult mouse cortical cell taxonomy revealed by single cell transcriptomics. Nat Neurosci 19:335-346
    Tran HTN, Ang KS, Chevrier M, Zhang X, Lee NYS, Goh M, Chen J (2020) A benchmark of batch-effect correction methods for single-cell RNA sequencing data. Genome Biol 21:12
    Van Eif VW, Devalla HD, Boink GJ, Christoffels VM (2018) Transcriptional regulation of the cardiac conduction system. Nat Rev Cardiol 15:617-630
    Vinogradova TM, Sirenko S, Lyashkov AE, Younes A, Li Y, Zhu W, Yang D, Ruknudin AM, Spurgeon H, Lakatta EG (2008) Constitutive phosphodiesterase activity restricts spontaneous beating rate of cardiac pacemaker cells by suppressing local Ca2+ releases. Circ Res 102:761-769
    Vinogradova TM, Brochet DX, Sirenko S, Li Y, Spurgeon H, Lakatta EG (2010) Sarcoplasmic reticulum Ca2+ pumping kinetics regulates timing of local Ca2+ releases and spontaneous beating rate of rabbit sinoatrial node pacemaker cells. Circ Res 107:767-775
    Zhu TG, Patel C, Martin S, Quan X, Wu Y, Burke JF, Chernick M, Kowey PR, Yan GX (2009) Ventricular transmural repolarization sequence:its relationship with ventricular relaxation and role in ventricular diastolic function. Eur Heart 30:372-380
    Zhu W, Wang C, Hu J, Wan R, Yu J, Xie J, Ma J, Guo L, Ge J, Qiu Y et al (2018) Ankyrin-B Q1283H variant linked to arrhythmias via loss of local protein phosphatase 2A activity causes ryanodine receptor hyperphosphorylation. Circulation 138:2682-2697
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