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Gating Effects of a Novel Allosteric Modulator at GluN1/GluN2A NMDA Receptors
Author(s) -
Chopra Divyan,
Irvine Mark,
Jane David,
Monaghan Daniel,
Dravid Shashank
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.933.3
Subject(s) - gating , nmda receptor , ionotropic effect , allosteric regulation , allosteric modulator , neuroscience , receptor , glutamate receptor , chemistry , patch clamp , biophysics , biology , biochemistry
NMDA receptors are members of the ionotropic glutamate receptor family and are critical for processes such as synaptic plasticity. They also represent important therapeutic targets for CNS disorders. However only a few NMDA receptor agents have successfully transitioned to clinical setting, thus there is a need to develop novel modulators preferably with different sites and mechanism of action which limit potential side effects. NMDA receptors are tetramers usually composed of two GluN1 and two GluN2 subunits. The goal of the current study was to evaluate the gating mechanisms of a novel allosteric modulator at the GluN1/GluN2A NMDA receptor. We used whole‐cell and cell‐attached patch recordings to evaluate the gating mechanism of a UBP series compound. In whole‐cell recordings we found that UBP684 increased the steady state current by 84.16±18%.We further performed cell‐attached recordings and observed that UBP684 increased the mean open time: control=1.57±0.53ms and UBP684=4.34±2.14ms and the open probability: control=0.08±0.02 and UBP684=0.61±0.15 and also reduced the mean shut times.The open time and shut time histograms were fitted with 3 and 5 exponential components respectively. UBP684 was found to primarily affect the area of the time constants and not the time constants themselves. Kinetic modeling suggests that UBP684 has a profound effect on one of the slower gating steps. Our studies indicate that UBP684 may have subunit‐selective effects and provides insight into a novel potentiating mechanism for GluN1/GluN2A NMDA receptors.