Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Excitotoxicity, driven by NMDA receptors (NMDARs), is traditionally linked to excessive intracellular calcium.
• However, NMDAR-mediated neurotoxicity can be prevented without altering NMDAR-induced calcium influx.

Purpose of the Study:

• To investigate the mechanism underlying NMDAR-mediated excitotoxicity.
• To identify therapeutic targets and develop small molecules to mitigate NMDAR-induced neurotoxicity.
• To explore the potential of targeting the NMDAR-TRPM4 interaction for treating neurodegenerative diseases.

Main Methods:

• Investigated the physical coupling between NMDARs and TRPM4 channels.
• Utilized structure-based computational drug screening to identify inhibitors of the NMDAR/TRPM4 interaction interface.
• Assessed the efficacy of identified inhibitors in cellular and mouse models of stroke and retinal degeneration.

Main Results:

• Excitotoxicity is dependent on the physical coupling of NMDARs to TRPM4, not solely on calcium signaling.
• Small molecules targeting the NMDAR/TRPM4 interface successfully disrupted the complex.
• Inhibitors reduced NMDA-triggered toxicity, mitochondrial dysfunction, CREB shutoff, and neuronal loss in disease models.
• Inhibitors preserved NMDAR-mediated calcium signaling while blocking toxicity.

Conclusions:

• The physical interaction between NMDARs and TRPM4 is a critical mediator of excitotoxicity.
• Targeting the NMDAR/TRPM4 interface with small molecules offers a promising therapeutic strategy.
• This approach may lead to treatments for currently intractable neurodegenerative conditions like stroke and retinal degeneration.