Phenylethanolamines inhibit NMDA receptors by enhancing proton inhibition.
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.
Mott
D D
DD
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. dmott@emory.edu
Doherty
J J
JJ
Zhang
S
S
Washburn
M S
MS
Fendley
M J
MJ
Lyuboslavsky
P
P
Traynelis
S F
SF
Dingledine
R
R
D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D006863:Hydrogen-Ion Concentration; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009865:Oocytes / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011522:Protons; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins; D014982:Xenopus laevis
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D010880:Piperidines; D011522:Protons; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; C095106:traxoprodil mesylate; C010739:ifenprodil