Subunit-specific mechanisms and proton sensitivity of NMDA receptor channel block

Shashank M. Dravid, Kevin Erreger, Hongjie Yuan, Katherine Nicholson, Phuong Le, Polina Lyuboslavsky, Antoine Almonte, Ernest Murray, Cara Mosely, Jeremy Barber, Adam French, Robert Balster, Thomas F. Murray, Stephen F. Traynelis

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Abstract

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 pKa 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.

Original languageEnglish (US)
Pages (from-to)107-128
Number of pages22
JournalJournal of Physiology
Volume581
Issue number1
DOIs
StatePublished - May 15 2007

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All Science Journal Classification (ASJC) codes

  • Physiology

Cite this

Dravid, S. M., Erreger, K., Yuan, H., Nicholson, K., Le, P., Lyuboslavsky, P., Almonte, A., Murray, E., Mosely, C., Barber, J., French, A., Balster, R., Murray, T. F., & Traynelis, S. F. (2007). Subunit-specific mechanisms and proton sensitivity of NMDA receptor channel block. Journal of Physiology, 581(1), 107-128. https://doi.org/10.1113/jphysiol.2006.124958