Apolipoprotein E receptor 2 interactions with the N-methyl-D-aspartate receptor

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Previous studies indicated apolipoprotein E (ApoE) activates neuronal ERK 1/2 signaling, blocked by low-density lipoprotein receptor family inhibitors, NMDA receptor antagonists, and calcium channel blockers.
• A hypothesis proposed an interaction between low-density lipoprotein receptor family members and NMDA receptors.

Purpose of the Study:

• To investigate the interaction between the apolipoprotein E receptor (ApoEr2) and NMDA receptors (NMDARs).
• To elucidate the role of postsynaptic density protein 95 (PSD95) in mediating these interactions.

Main Methods:

• Co-immunoprecipitation experiments to confirm protein interactions.
• Analysis of protein domains involved in binding.
• Investigation of protein interactions in neuronal cultures.
• Assessment of protein cleavage and secretion.

Main Results:

• Confirmed extracellular domain interaction between ApoEr2 and NMDAR1.
• Identified interaction between PSD95's PDZ1 domain and ApoEr2's C terminus via an alternatively spliced exon.
• Showed NMDA receptor activation and ApoEr2 ligand modulate ApoEr2-PSD95 interaction.
• Found PSD95's PDZ2 domain interacts with NMDAR2A and NMDAR2B subunits.
• Demonstrated full-length PSD95 increases cell surface ApoEr2 levels, cleavage, and secretion of ApoEr2 fragments.

Conclusions:

• ApoEr2 forms a multiprotein complex with NMDA receptor subunits and PSD95.
• This complex formation is regulated by NMDA receptor activity and ligand binding.
• PSD95 plays a crucial role in scaffolding ApoEr2 and NMDARs in the postsynaptic density.