Glutamate drives 'local Ca2+ release' in cardiac pacemaker cells

The sinoatrial node (SAN) is the origin of the electrical signals for rhythmic heartbeats in mammals. The spontaneous firing of SAN pacemaker cells (SANPCs) triggers cardiac contraction. 'Local Ca2+ release' (LCR), a unique cellular activity, acts as the 'engine' of the spontaneous firing of SANPCs. However, the mechanism of LCR initiation remains unclear. Here, we report that endogenous glutamate drives LCRs in SANPCs. Using a glutamate sensor, we unraveled a tight correlation between glutamate accumulation and LCR occurrence, indicating a potential relationship between glutamate and LCRs. Intracellular application of glutamate significantly enhanced the LCRs in both intact and permeabilized SANPCs. Mechanistically, we revealed that mitochondrial excitatory amino acid transporter 1 (EAAT1)-dependent mitochondrial glutamate import promoted ROS generation, which in turn led to the oxidation of Ca2+-handling proteins, ultimately resulting in enhanced LCRs. Importantly, EAAT1 depletion reduced both the spontaneous firing rates of isolated SANPCs and the heart rate in vitro and in vivo, suggesting the central role of EAAT1 as a glutamate transporter in the regulation of cardiac autonomic rhythm. In conclusion, our results indicate that glutamate serves as an LCR igniter in SANPCs, adding a potentially important element to the coupled-clock theory that explains the origin of spontaneous firing. These findings shed new light on the future prevention and treatment of cardiac pacemaker cell-related arrhythmias.

Automated summary

The study reveals the role of glutamate in driving local Ca2+ release (LCR) in sinoatrial node pacemaker cells (SANPCs), adding a potentially important element to the coupled-clock theory of spontaneous firing origin. Mitochondrial excitatory amino acid transporter 1 (EAAT1) mediates mitochondrial glutamate import, promoting ROS generation and enhancing LCR. Depletion of EAAT1 reduces spontaneous firing rates of isolated pacemaker cells and heart rate, highlighting the central role of EAAT1 as a glutamate transporter in regulating cardiac autonomic rhythm.