Volume 31, No 9, Sep 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 9, September 2021: 951-964   |  Open Access

ORIGINAL ARTICLES

Identification of an endogenous glutamatergic transmitter system controlling excitability and conductivity of atrial cardiomyocytes

Duanyang Xie^1,2,3 , Ke Xiong^1,2,3 , Xuling Su^2,3 , Guanghua Wang^2,3 , Qiang Ji⁴ , Qicheng Zou^2,3 , Lingling Wang^2,5 , Yi Liu^1,2,3 , Dandan Liang^1,2,3 , Jinfeng Xue^6,7 , Luxin Wang^1,2 , Xueting Gao^1,2 , Xingdong Gu^2,5 , Hongyu Liu^1,2 , Xiaoyu He^1,2 , Li Li^2,3,8 , Jian Yang^2,3 , Youming Lu⁹ , Luying Peng^2,3,8 , Yi-Han Chen^1,2,3,8,*

¹Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China
²Key Laboratory of Arrhythmias of the Ministry of Education of China, Tongji University School of Medicine, Shanghai 200120, China
³Institute of Medical Genetics, Tongji University, Shanghai 200092, China
⁴Department of Cardiovascular Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
⁵Jinzhou Medical University, Jinzhou, Liaoning 121000, China
⁶Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200092, China
⁷Reproductive Medicine Center, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
⁸Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China
⁹Institute for Brain Research, Wuhan Center of Brain Science, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
These authors contributed equally: Duanyang Xie, Ke Xiong, Xuling Su, Guanghua Wang, Qiang Ji Correspondence: Yi-Han Chen(yihanchen@tongji.edu.cn)

As an excitatory transmitter system, the glutamatergic transmitter system controls excitability and conductivity of neurons. Since both cardiomyocytes and neurons are excitable cells, we hypothesized that cardiomyocytes may also be regulated by a similar system. Here, we have demonstrated that atrial cardiomyocytes have an intrinsic glutamatergic transmitter system, which regulates the generation and propagation of action potentials. First, there are abundant vesicles containing glutamate beneath the plasma membrane of rat atrial cardiomyocytes. Second, rat atrial cardiomyocytes express key elements of the glutamatergic transmitter system, such as the glutamate metabolic enzyme, ionotropic glutamate receptors (iGluRs), and glutamate transporters. Third, iGluR agonists evoke iGluR-gated currents and decrease the threshold of electrical excitability in rat atrial cardiomyocytes. Fourth, iGluR antagonists strikingly attenuate the conduction velocity of electrical impulses in rat atrial myocardium both in vitro and in vivo. Knockdown of GRIA3 or GRIN1, two highly expressed iGluR subtypes in atria, drastically decreased the excitatory firing rate and slowed down the electrical conduction velocity in cultured human induced pluripotent stem cell (iPSC)-derived atrial cardiomyocyte monolayers. Finally, iGluR antagonists effectively prevent and terminate atrial fibrillation in a rat isolated heart model. In addition, the key elements of the glutamatergic transmitter system are also present and show electrophysiological functions in human atrial cardiomyocytes. In conclusion, our data reveal an intrinsic glutamatergic transmitter system directly modulating excitability and conductivity of atrial cardiomyocytes through controlling iGluR-gated currents. Manipulation of this system may open potential new avenues for therapeutic intervention of cardiac arrhythmias.

https://doi.org/10.1038/s41422-021-00499-5

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