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

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.

Transcriptomic Profiling of Canine Atrial Fibrillation Models After One Week of Sustained Arrhythmia

“… 48 Moreover, a recent study has shown fundamental roles for glutamatergic receptors in rat atrial cardiomyocytes and induced pluripotent stem cell-derived atrial cardiomyocytes, including a reduction in cardiomyocyte excitability after GRIA3 knockdown. 49 Therefore, the DLK1-DIO3 miRNA cluster may be an adaptative regulator of cardiomyocyte excitability or of neural cells in the presence of AF.…”

The Emerging Role of N-Methyl-D-Aspartate (NMDA) Receptors in the Cardiovascular System: Physiological Implications, Pathological Consequences, and Therapeutic Perspectives

“…Preliminary investigations revealed that GluN1 was expressed in both monkey [ 33 ] and rat [ 34 ] hearts, in which they were enriched in the conducting system, in atrial and ventricular cardiomyocytes, in the wall of coronary blood vessels, in coronary cardiac intramural nerve terminals, and in cardiac ganglia [ 32 ]. Subsequently, GluN1 expression was confirmed in the same anatomic sites of human myocardium [ 35 ], which can also express GluN2C [ 36 ] and GluN3 [ 37 ]. Finally, a recent transcriptomic analysis showed that all GluN subunits are expressed in rat atria [ 37 ].…”

Human-induced pluripotent stem cell-atrial-specific cardiomyocytes and atrial fibrillation

“…Since CMs and neurons are both excitable cells, CMs may be controlled by a similar mechanism. Xie et al [ 72 ] found that aCMs have an intrinsic glutamatergic transmitter system that governs AP production and propagation. There are many glutamate-containing vesicles beneath the plasma membrane of rat atrial CMs.…”