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

Area of Science:

• Cardiovascular Physiology
• Cellular Electrophysiology
• Molecular Cardiology

Background:

• The sinoatrial node (SAN) generates rhythmic heartbeats via spontaneous firing of its pacemaker cells (SANPCs).
• Local calcium release (LCR) is the key cellular mechanism driving SANPC spontaneous firing.
• The precise initiation mechanism of LCRs in SANPCs remains poorly understood.

Purpose of the Study:

• To elucidate the mechanism underlying the initiation of local calcium release (LCR) in sinoatrial node pacemaker cells (SANPCs).
• To investigate the role of endogenous glutamate in regulating SANPC activity and cardiac rhythm.

Main Methods:

• Utilized a glutamate sensor to correlate glutamate accumulation with LCR occurrence in SANPCs.
• Performed intracellular glutamate application experiments on intact and permeabilized SANPCs.
• Investigated the role of mitochondrial excitatory amino acid transporter 1 (EAAT1) in glutamate import, ROS generation, and Ca2+-handling protein oxidation.

Main Results:

• Demonstrated a strong correlation between glutamate accumulation and LCR occurrence in SANPCs.
• Showed that intracellular glutamate application significantly enhanced LCRs.
• Identified EAAT1-dependent mitochondrial glutamate import as a driver of ROS generation, leading to enhanced LCRs and reduced SANPC firing and heart rate upon EAAT1 depletion.

Conclusions:

• Endogenous glutamate acts as a critical initiator of LCRs in SANPCs, functioning as the 'engine' for spontaneous firing.
• The EAAT1 transporter plays a crucial role in regulating cardiac autonomic rhythm by mediating glutamate's effects on LCRs.
• These findings offer new insights into the coupled-clock theory and potential therapeutic targets for cardiac arrhythmias.