Fig. 1: Molecular mechanisms mediated by excitotoxicity. | Acta Pharmacologica Sinica

Fig. 1: Molecular mechanisms mediated by excitotoxicity.

From: Molecular mechanisms of excitotoxicity and their relevance to the pathogenesis of neurodegenerative diseases—an update

Fig. 1

The excitotoxicity-induced pathological process in neurons represents a complex cascade with extensive crosstalk among cellular systems. Firstly, glutamate over-activation of ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs) triggers massive Ca²⁺ influx, disrupting dynamics of glutamate receptors and intracellular Ca²⁺ homeostasis. Secondly, mitochondrial Ca²⁺ overload activates mitochondrial permeability transition pore (mPTP) opening, changes ΔΨm, and triggers reactive oxygen species (ROS) production. Drp1-mediated excessive division and PINK1/Parkin pathway-mediated mitophagy lead to mitochondrial dynamic imbalance and reduced adenosine triphosphate (ATP) production. ATP deficiency affects both endoplasmic reticulum stress (ERS) and intracellular nicotinamide adenine dinucleotide (NAD+) metabolism. On the one hand, because the ER needs ATP for protein folding, ATP deficiency activates UPR and protein misfolding, resulting in ERS. On the other hand, ATP reduction leads to the activation of PARP-1 to participate in repair. However, activation of PARP-1 will consume a large amount of NAD+, and eventually, the intracellular NAD+ metabolism is unbalanced.

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