Glutamate drives ‘local Ca2+ release’ in cardiac pacemaker cells

Abstract

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.

Integrated Metabolomics and Network Pharmacology Investigation of Cardioprotective Effects of Myricetin after 1-Week High-Intensity Exercise

“…The metabolic pathways with high enrichment were the FoxO pathway, glutamate metabolism, pentose phosphate pathway, and central carbon metabolism. The visualization of the commonly enriched pathways according to network pharmacology and metabolomics, as well as their included therapeutic targets and differential metabolites, demonstrated an extensive myocardial metabolic modulation and cardiac protection effect by myricetin [ 30 , 31 , 32 ].…”

A new diagnostic tool for brain disorders: extracellular vesicles derived from neuron, astrocyte, and oligodendrocyte

“…Most methods for capturing ADEs utilize anti-GLAST antibodies, as GLAST is considered to be predominantly expressed in astrocytes. However, GLAST is also moderately expressed in the heart ( Xie et al, 2022 ), ovary, and placenta (see text footnote 3). Aquaporin 4 (AQP4) and Glial Fibrillary Acidic Protein (GFAP), two classical astrocyte markers, have been tested for capturing ADEs by flow cytometry.…”

Illuminating Anions in Biology with Genetically Encoded Fluorescent Biosensors

“…For example, glutamate is a key excitatory neurotransmitter that is coupled to calcium transients in sinoatrial node pacemaker cells (SANPCs) [68]. To visualize this, SANPCs expressing the well-established iGluSnFr on the cytosolic face of the plasma membrane were stained with the red calcium dye Cal-590 (Figure 3c) [68]. Glutamate accumulation in the cytosol correlated to local calcium release (LCR).…”

“…The true test of a biosensor lies in the hands of a new end user who seeks to apply an established biosensor in previously unexplored contexts [68,[74][75][76]. This was demonstrated by Herstel et al with SuperClomeleon, a Cerulean-Topaz FRET biosensor from 2013 [77,78].…”