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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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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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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DOI: https://doi.org/10.1038/3661