Multiple effects of copper on NMDA receptor currents

Area of Science:

• Neuroscience
• Neurochemistry
• Molecular Biology

Background:

• Copper (Cu) is vital for the human brain, released from synaptic vesicles.
• Copper is known to inhibit NMDA receptor (NR) currents with an IC50 of approximately 20 µM.

Purpose of the Study:

• To investigate the dual effect of copper on NMDA receptor currents.
• To explore the concentration-dependent potentiation and inhibition of NR currents by copper.
• To elucidate the role of the NR amino terminal domain in copper's interaction.

Main Methods:

• Electrophysiological recordings in cultured neonatal rat cerebellum granule cells (CGCs).
• Studies in transiently transfected HEK293 cells expressing GluN1/GLUN2A or GluN1/GluN2B receptors.
• Calcium imaging using Fura2 in CGCs and analysis of receptor mutants.

Main Results:

• Copper potentiated NR currents in CGCs (EC50=4.6 µM) and HEK293 cells (GluN1/GLUN2A: EC50=2 µM; GluN1/GluN2B: potentiation at 10 µM).
• Copper inhibited NR currents at higher concentrations (CGCs: IC50=24 µM; GluN1/GLUN2A: IC50=26 µM; GluN1/GluN2B: inhibition at 100 µM).
• Facilitation of NMDA-driven calcium influx was observed and prevented by DTT; potentiation was absent in ATD-deleted mutants.

Conclusions:

• Copper exhibits a dual role, facilitating NR current at lower concentrations and blocking it at higher concentrations.
• The N-terminal domain of NMDA receptors is crucial for the observed potentiation by copper.
• These findings have implications for understanding copper's role in synaptic and extrasynaptic activity.