Different oxysterols have opposing actions at N-methyl-d-aspartate receptors

Andrew J. Linsenbardt, Amanda Taylor, Christine M. Emnett, James J. Doherty, Kathiresan Krishnan, Douglas F. Covey, Steven M. Paul, Charles F. Zorumski, Steven Mennerick

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Oxysterols have emerged as important biomarkers in disease and as signaling molecules. We recently showed that the oxysterol 24(S)-hydroxycholesterol, the major brain cholesterol metabolite, potently and selectively enhances NMDA receptor function at a site distinct from other modulators. Here we further characterize the pharmacological mechanisms of 24(S)-hydroxycholesterol and its synthetic analog SGE201. We describe an oxysterol antagonist of this positive allosteric modulation, 25-hydroxycholesterol. We found that 24(S)- hydroxycholesterol and SGE201 primarily increased the efficacy of NMDAR agonists but did not directly gate the channel or increase functional receptor number. Rather than binding to a direct aqueous-accessible site, oxysterols may partition into the plasma membrane to access the NMDAR, likely explaining slow onset and offset kinetics of modulation. Interestingly, oxysterols were ineffective when applied to the cytosolic face of inside-out membrane patches or through a whole-cell pipette solution, suggesting a non-intracellular site. We also found that another natural oxysterol, 25-hydroxycholesterol, although exhibiting slight potentiation on its own, non-competitively and enantioselectively antagonized the effects of 24(S)-hydroxycholesterol analogs. In summary, we suggest two novel allosteric sites on NMDARs that separately modulate channel gating, but together oppose each other.

Original languageEnglish
Pages (from-to)232-242
Number of pages11
JournalNeuropharmacology
Volume85
DOIs
StatePublished - Oct 2014

Keywords

  • Allosteric
  • Gating
  • Modulation
  • NMDA receptor
  • Neurodegeneration

Fingerprint Dive into the research topics of 'Different oxysterols have opposing actions at N-methyl-d-aspartate receptors'. Together they form a unique fingerprint.

  • Cite this