1. Identification of an endogenous glutamatergic transmitter system controlling excitability and conductivity of atrial cardiomyocytes
- Author
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Li Li, Hongyu Liu, Yi-Han Chen, Qicheng Zou, Jian Yang, Youming Lu, Xingdong Gu, Ke Xiong, Qiang Ji, Luying Peng, Dandan Liang, Jinfeng Xue, Lingling Wang, Xiaoyu He, Duanyang Xie, Luxin Wang, Xuling Su, Yi Liu, Guanghua Wang, and Xueting Gao
- Subjects
Induced Pluripotent Stem Cells ,Action Potentials ,Endogeny ,030204 cardiovascular system & hematology ,Article ,03 medical and health sciences ,Glutamatergic ,0302 clinical medicine ,Atrial Fibrillation ,Animals ,Humans ,Myocytes, Cardiac ,Heart Atria ,GRIA3 ,Induced pluripotent stem cell ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,biology ,Glutamate receptor ,Cell Biology ,Rats ,Cell biology ,Electrophysiology ,cardiovascular system ,biology.protein ,Excitatory postsynaptic potential ,Ionotropic effect - Abstract
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.
- Published
- 2021