TY - JOUR T1 - Non-competitive, Voltage-dependent NMDA Receptor Antagonism by Hydrophobic Anions JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.112.081794 SP - mol.112.081794 AU - Andrew Linsenbardt AU - Mariangela Chisari AU - Andrew Yu AU - Hong-Jin Shu AU - Charles F. Zorumski AU - Steven J. Mennerick Y1 - 2012/11/09 UR - http://molpharm.aspetjournals.org/content/early/2012/11/09/mol.112.081794.abstract N2 - NMDA receptor (NMDAR) antagonists are dissociative anesthetics, drugs of abuse, and are of therapeutic interest in neurodegeneration and neuropsychiatric disease. Many well-known NMDAR antagonists are positively charged, voltage-dependent channel blockers. We recently showed that the hydrophobic anion dipicrylamine (DPA) negatively regulates GABAA receptor function by a mechanism indistinguishable from that of sulfated neurosteroids. Because sulfated neurosteroids also modulate NMDARs, here we examined DPA's effects on NMDAR function. In rat hippocampal neurons DPA inhibited currents gated by 300 μM NMDA with an IC50 of 2.3 μM. Neither onset nor offset of antagonism exhibited dependence on channel activation but exhibited a non-competitive profile. DPA antagonism was independent of NMDAR subunit composition and was similar at extrasynaptic and total receptor populations. Surprisingly, like cationic channel blockers but unlike sulfated neurosteroids, DPA antagonism was voltage dependent. Onset and offset of DPA antagonism were nearly 10-fold faster than DPA-induced increases in membrane capacitance, suggesting that membrane interactions do not directly explain antagonism. Further, voltage dependence did not derive from association of DPA with a site on NMDARs directly accessible to the outer membrane leaflet, assessed by DPA translocation experiments. Consistent with the expected lack of channel block, DPA antagonism did not interact with permeant ions. Therefore, we speculate that voltage dependence may arise from interactions of DPA with the inherent voltage dependence of channel gating. Overall, we conclude that DPA non-competitively inhibits NMDA-induced current by a novel voltage-dependent mechanism and represents a new class of anionic NMDAR antagonists. ER -