17-β-Estradiol (E2) is a steroid hormone involved in neuroprotection against excitotoxicity and other forms of brain injury.Through genomic and non-genomic mechanisms, E2 modulates neuronal excitability and rapidly increases signal transmission by regulating N-methyl-D-aspartate (NMDA) and non-NMDA receptors.The potential neuroprotective role of estradiol in chronic neurodegenerative disorders and acute brain ischemia following cardiac arrest and stroke is of great therapeutic interest.However, the mechanisms and identity of the receptors involved remain unclear, although it has been suggested that G-protein-coupled receptor 30 (GPR30) is linked to protection against ischemic insults.In this study, rapid nongenomic neuroprotection by GPR30 stimulation was examined in culture cortical neurons.Both E2 and the GPR30 agonist G1 attenuated the excitotoxicity induced by NMDA receptor stimulation.The acute neuroprotection induced by GPR30 stimulation was dependent on G-protein coupled signaling and ERK1/2 activation, but independent of gene transcription and protein synthesis.Knockdown of GPR30 by transfection with small interfering RNAs (siRNAs) significantly reduced E2-induced rapid neuro-protection.Patch-clamp recordings revealed that the activation of GPR30 significantly depressed exogenous NMDA-elicited currents.