Caveolin-1 Attenuates Excitotoxic Signaling by Regulating NMDA, AMPA, and Kainate Receptor-Mediated Calcium Influx in Hippocampal Neuronal Cultures.

Glutamate excitotoxicity is a critical pathological mechanism underlying neuronal death in ischemic stroke, epilepsy, and neurodegenerative diseases. Caveolin-1 (Cav-1), a structural protein of caveolae membrane microdomains, has emerged as a potential modulator of neuronal survival, yet its precise mechanisms in excitotoxicity remain incompletely understood. In this study, we investigated the role of Cav-1 in regulating glutamate-induced calcium dysregulation, reactive oxygen species (ROS) generation, and mitochondrial dysfunction in primary hippocampal neurons. Using Cav-1 overexpression (Cav-1OE) and Cav-1 knockdown (Cav-1KD) approaches, we demonstrate that Cav-1OE significantly attenuates glutamate-stimulated intracellular Ca2+ elevation, reduces ROS generation, and prevents mitochondrial membrane potential (Ψm) depolarization. Further investigation revealed that Cav-1OE reduces, while Cav-1KD enhances, calcium responses mediated by NMDA, AMPA, and KA receptors. These findings establish that Cav-1 functionally attenuates excitotoxic signaling by negatively regulating ionotropic glutamate receptor-mediated Ca2+ influx.