RT Journal Article
SR Electronic
T1 Non-competitive, Voltage-dependent NMDA Receptor Antagonism by Hydrophobic Anions
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.112.081794
DO 10.1124/mol.112.081794
A1 Andrew Linsenbardt
A1 Mariangela Chisari
A1 Andrew Yu
A1 Hong-Jin Shu
A1 Charles F. Zorumski
A1 Steven J. Mennerick
YR 2012
UL http://molpharm.aspetjournals.org/content/early/2012/11/09/mol.112.081794.abstract
AB 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.