The receptor-receptor interaction between mGluR1 receptor and NMDA receptor: a potential therapeutic target for protection against ischemic stroke

Ischemic stroke is one of the leading causes of long-term disability worldwide. It arises when the blood flow to the brain is severely impaired, causing brain infarction. The current therapies for ischemic stroke are tissue plasminogen activator and mechanical thrombectomy, which re-establishes blood circulation to the brain but offers no neuroprotective effects. Excitotoxicity, particularly through the N-methyl-D-aspartate receptor (NMDAR), has been heavily implicated in the pathophysiology of brain infarction resulting from ischemic stroke. Here we investigated the interaction between NMDAR and metabotropic glutamate receptor 1 (mGluR1) as a novel target to develop potential neuroprotective agents for ischemic stroke. Through coimmunoprecipitation and affinity binding assay, we revealed that the interaction is mediated through 2 distinct sites on the mGluR1 C terminus. We then found that the disruption of mGluR1-G1uN2A subunit of NMDAR (G1uN2A) protected the primary mouse hippocampal neurons against NMDAR-mediated excitotoxicity and reversed the NMDAR-mediated regulation of ERK1/2 in rat hippocampal slices. The same protection was also observed in an animal model of ischemic stroke, alleviating brain infarction and yielding better motor recovery. These findings confirmed the existence of a receptor-receptor interaction between NMDAR and mGluR1, implicating this interconnection as a potential treatment target site for ischemic stroke.