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This Article Full Text Full Text (PDF) All Versions of this Article: 581/1/107    most recent jphysiol.2006.124958v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dravid, S. M. Articles by Traynelis, S. F. Search for Related Content PubMed PubMed Citation Articles by Dravid, S. M. Articles by Traynelis, S. F. Related Collections Neuroscience Related Article

¹ Departments of Pharmacology and
⁴ Chemistry, Emory University, Atlanta, GA 30322, USA
² Department of Molecular Physiology and Biophysics, Vanderbilt University, 465 21st Avenue S, MRB III Room 7124, Nashville, TN 37232, USA
³ Department of Pharmacology and Toxicology and
⁵ Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA 23298, USA
⁶ Department of Pharmacology, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA

We have compared the potencies of structurally distinct channel blockers at recombinant NR1/NR2A, NR1/NR2B, NR1/NR2C and NR1/NR2D receptors. The IC₅₀ values varied with stereochemistry and subunit composition, suggesting that it may be possible to design subunit-selective channel blockers. For dizocilpine (MK-801), the differential potency of MK-801 stereoisomers determined at recombinant NMDA receptors was confirmed at native receptors in vitro and in vivo. Since the proton sensor is tightly linked both structurally and functionally to channel gating, we examined whether blocking molecules that interact in the channel pore with the gating machinery can differentially sense protonation of the receptor. Blockers capable of remaining trapped in the pore during agonist unbinding showed the strongest dependence on extracellular pH, appearing more potent at acidic pH values that promote channel closure. Determination of pK_a values for channel blockers suggests that the ionization of ketamine but not of other blockers can influence its pH-dependent potency. Kinetic modelling and single channel studies suggest that the pH-dependent block of NR1/NR2A by (–)MK-801 but not (+)MK-801 reflects an increase in the MK-801 association rate even though protons reduce channel open probability and thus MK-801 access to its binding site. Allosteric modulators that alter pH sensitivity alter the potency of MK-801, supporting the interpretation that the pH sensitivity of MK-801 binding reflects the changes at the proton sensor rather than a secondary effect of pH. These data suggest a tight coupling between the proton sensor and the ion channel gate as well as unique subunit-specific mechanisms of channel block.

(Received 14 November 2006; accepted after revision 8 February 2007; first published online 15 February 2007)
Corresponding author S. Dravid: Department of Pharmacology, Emory University School of Medicine, Rollins Research Centre, 1510 Clifton Road, Atlanta, GA 30322-3090, USA. Email: smdravid{at}pharm.emory.edu

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