N-methyl-D-aspartate receptor inhibition by an apolipoprotein E-derived peptide relies on low-density lipoprotein receptor-associated protein

Neuropharmacology. 2008 Aug;55(2):204-14. doi: 10.1016/j.neuropharm.2008.05.016. Epub 2008 May 24.


The effects of a synthetic apoE peptide, viz., residues 133-149 (apoE[133-149]), a mimetic that comprises the apoE receptor binding domain, on N-methyl-D-aspartate (NMDA)/glycine-induced ion flow through NMDA receptor (NMDAR) channels, have been investigated. The activity of apoE[133-149] was found to depend on the low-density lipoprotein receptor-related protein (LRP). Competition experiments with receptor-associated protein (RAP) and activated alpha(2)-macroglobulin (alpha(2)M*), two proteins that compete for apoE binding to LRP, demonstrate that apoE[133-149] inhibition of NMDAR function is mediated at a locus in LRP that overlaps with the binding sites of RAP and alpha(2)M*. A coreceptor of LRP, cell surface heparin sulfate proteoglycan, did not function in this system. Additional electrophysiology experiments demonstrated that the inhibitory potency of apoE[133-149] was threefold greater for NMDAR-transfected wild-type Chinese hamster ovary (CHO) cells compared with NMDAR-transfected CHO cells deficient in LRP. Studies with truncation and replacement variants of the apoE peptide demonstrated that the NMDAR inhibitory properties of these peptides correlate with their binding affinities for LRP. These novel results indicate that apoE functions as an inhibitor of NMDAR ion channels indirectly via LRP, and are suggestive of a participatory role for LRP in NMDAR-based neuropathies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apolipoproteins E / chemistry*
  • Binding Sites / drug effects
  • Cell Line, Transformed
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cricetinae
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Dose-Response Relationship, Radiation
  • Drug Interactions
  • Glycine / pharmacology
  • Humans
  • LDL-Receptor Related Proteins / metabolism*
  • LDL-Receptor Related Proteins / pharmacology
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Membrane Potentials / radiation effects
  • N-Methylaspartate / pharmacology
  • Patch-Clamp Techniques / methods
  • Peptide Fragments / pharmacology*
  • Protein Binding / drug effects
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Spermine / pharmacology
  • Transfection / methods


  • Apolipoproteins E
  • LDL-Receptor Related Proteins
  • Peptide Fragments
  • Receptors, N-Methyl-D-Aspartate
  • Spermine
  • N-Methylaspartate
  • Glycine