Title | Different oxysterols have opposing actions at N-methyl-D-aspartate receptors. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Linsenbardt AJ, Taylor A, Emnett CM, Doherty JJ, Krishnan K, Covey DF, Paul SM, Zorumski CF, Mennerick S |
Journal | Neuropharmacology |
Volume | 85 |
Pagination | 232-42 |
Date Published | 2014 Oct |
ISSN | 1873-7064 |
Keywords | Animals, Cell Membrane, Cells, Cultured, Cytosol, Dizocilpine Maleate, Dose-Response Relationship, Drug, Excitatory Amino Acid Agents, Excitatory Amino Acid Agonists, Female, Hippocampus, Hydroxycholesterols, Kinetics, Male, Membrane Potentials, Neurons, Oocytes, Patch-Clamp Techniques, Rats, Sprague-Dawley, Receptors, N-Methyl-D-Aspartate, Xenopus laevis |
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. |
DOI | 10.1016/j.neuropharm.2014.05.027 |
Alternate Journal | Neuropharmacology |
PubMed ID | 24878244 |
PubMed Central ID | PMC4107067 |
Grant List | AA017413 / AA / NIAAA NIH HHS / United States GM47969 / GM / NIGMS NIH HHS / United States MH077791 / MH / NIMH NIH HHS / United States MH078823 / MH / NIMH NIH HHS / United States P01 GM047969 / GM / NIGMS NIH HHS / United States R01 AA017413 / AA / NIAAA NIH HHS / United States R01 MH077791 / MH / NIMH NIH HHS / United States R01 MH078823 / MH / NIMH NIH HHS / United States R01 MH101874 / MH / NIMH NIH HHS / United States T32 DA007261 / DA / NIDA NIH HHS / United States T32 DA007261 / DA / NIDA NIH HHS / United States |