Effect of ifenprodil on GluN1/GluN2B N-Methyl-D-aspartate receptor gating

Jay M. Bhatt, Anand Prakash, Pratyush S. Suryavanshi, Shashank M. Dravid

Research output: Contribution to journalArticle

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Abstract

Ifenprodil is an allosteric inhibitor of GluN1/GluN2B N-methyl-D-aspartate receptors. Despite its widespread use as a prototype for drug development and a subtype-selective tool for physiologic experiments, its precise effect on GluN1/GluN2B gating is yet to be fully understood. Interestingly, recent crystallographic evidence identified that ifenprodil, unlike zinc, binds at the interface of the GluN1/GluN2B amino terminal domain dimer by an induced-fit mechanism. To delineate the effect of this unique binding on GluN1/GluN2B receptor gating, we recorded steadystate currents from cell-attached and outside-out patches. At pH 7.9 in cell-attached patches, ifenprodil increased the occupancy of the long-lived shut conformations, thereby reducing the open probability of the receptor with no change in the mean open time. In addition, ifenprodil selectively affected the area of shut time constants, but not the time constants themselves. Kinetic analyses suggested that ifenprodil prevents the transition of the receptor to an open state and increases its dwell time in an intrinsically occurring closed conformation or desensitized state. We found distinct differences in the action of ifenprodil at GluN1/GluN2B in comparison with previous studies on the effect of zinc on GluN1/GluN2A gating, which may arise due to their unique binding sites. Our data also uncover the potential pH-dependent action of ifenprodil on gating. At a low pH (pH 7.4), but not pH 7.9, ifenprodil reduces the mean open time of GluN1/GluN2B receptors, which may be responsible for its usefulness as a context-dependent inhibitor in conditions like ischemia and stroke, when the pH of the extracellular milieu becomes acidic.

Original languageEnglish
Pages (from-to)9-21
Number of pages13
JournalMolecular Pharmacology
Volume83
Issue number1
DOIs
StatePublished - Jan 2013

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N-Methyl-D-Aspartate Receptors
Zinc
ifenprodil
Ischemia
Stroke
Binding Sites
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Molecular Medicine

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Effect of ifenprodil on GluN1/GluN2B N-Methyl-D-aspartate receptor gating. / Bhatt, Jay M.; Prakash, Anand; Suryavanshi, Pratyush S.; Dravid, Shashank M.

In: Molecular Pharmacology, Vol. 83, No. 1, 01.2013, p. 9-21.

Research output: Contribution to journalArticle

Bhatt, Jay M. ; Prakash, Anand ; Suryavanshi, Pratyush S. ; Dravid, Shashank M. / Effect of ifenprodil on GluN1/GluN2B N-Methyl-D-aspartate receptor gating. In: Molecular Pharmacology. 2013 ; Vol. 83, No. 1. pp. 9-21.
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