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Phenylethanolamines inhibit NMDA receptors by enhancing proton inhibition

Nature Neuroscience volume 1, pages 659–667 (1998)Cite this article

Abstract

The phenylethanolamines, ifenprodil and CP-101,606, are NMDA receptor antagonists with promising neuroprotective properties. In recombinant NMDA receptors expressed in Xenopus oocytes, we found that these drugs inhibit NMDA receptors through a unique mechanism, making the receptor more sensitive to inhibition by protons, an endogenous negative modulator. These findings support a critical role for the proton sensor in gating the NMDA receptor and point the way to identifying a context-dependent NMDA receptor antagonist that is inactive at physiological pH, but is a potent inhibitor during the acidic conditions that arise during epilepsy, ischemia and brain trauma.

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Figure 1: CP-101,606 and ifenprodil inhibit NMDA receptors in a subunit selective and noncompetitive fashion.
Figure 2: Phenylethanolamines enhance proton inhibition of the NMDA receptor.
Figure 3: Alkaline pH reduces ifenprodil inhibition but not ifenprodil binding.
Figure 4: Equivalent effect of NR1-1a mutations on inhibition by protons and ifenprodil.
Figure 5: Spermine and exon 5 synergistically reduce inhibition by CP-101,606.
Figure 6: Ifenprodil and CP-101,606 differ in their pH dependence.
Figure 7: Schematic diagram of the proposed interaction between phenylethanolamines, spermine, exon 5 and the proton sensor (Xδ–).

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Acknowledgements

We thank Pfizer, Inc. for the gift of CP-101,606, S. Nakanishi, K. Moriyoshi, Stephen Heinemann and Keith Williams for NMDA receptor clones or mutants, James B. Revennaugh for technical assistance, Nancy F. Ciliax for preparing neuronal cultures and Kimberley Lindsey for work on early neuroprotection experiments. We also thank Keith Williams for pointing out the pH dependence of the E181Q mutation and for comments on the manuscript. This work was supported by AES/EFA Fellowships (D.D.M. and J.J.D.), the NIH (R.D. and S.F.T.), the John Merck Fund (S.F.T.) and Bristol-Myers Squibb (R.D.).

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  1. Department of Pharmacology, Emory University School of Medicine, Rollins Research Building, 1510 Clifton Road, Atlanta, 30322, Georgia, USA

    David D. Mott, James J. Doherty, Sunan Zhang, Mark S. Washburn, Morris J. Fendley, Polina Lyuboslavsky, Stephen F. Traynelis & Raymond Dingledine

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Mott, D., Doherty, J., Zhang, S. et al. Phenylethanolamines inhibit NMDA receptors by enhancing proton inhibition . Nat Neurosci 1, 659–667 (1998). https://doi.org/10.1038/3661

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