Phenylethanolamines inhibit NMDA receptors by enhancing proton inhibition

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

doi:10.1038/3661

Cited by 205 publications

(209 citation statements)

References 37 publications

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“…The finding that protons appear to shift receptors to an inactive state also carries structural implications and suggests that other forms of allosteric modulation could proceed through creation of briefly occupied inactive states [e.g., calcineurin effects on GluR1 (Banke et al, 2000)]. Given that a number of regulators, such as polyamines, extracellular Zn 2ϩ , ifenprodil, and alternative splicing, all appear to alter NMDA receptor function by shifting the pKa of the proton sensor (Traynelis et al, 1995;Mott et al, 1998;Choi and Lipton, 1999;Low et al, 2000), our findings have widespread implications for NMDA receptor function.…”

Section: Discussionmentioning

confidence: 99%

“…Allosteric regulators such as polyamines acting at NR1/NR2B NMDA receptors (Traynelis et al, 1995), ifenprodil acting at NR1/NR2B (Mott et al, 1998), and zinc acting at NR1/NR2A (Choi and Lipton, 1999;Low et al, 2000;Paoletti et al, 2000 have been proposed to exert their actions through modification of tonic inhibition by physiological pH. Thus, proton-sensitive gating could be a downstream feature of receptor activation that is regulated by exogenous molecules and therapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

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Protons Trap NR1/NR2B NMDA Receptors in a Nonconducting State

Banke¹,

Dravid²,

Traynelis³

2005

J. Neurosci.

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NMDA receptors are highly expressed in the CNS and are involved in excitatory synaptic transmission, as well as synaptic plasticity. Given that overstimulation of NMDA receptors can cause cell death, it is not surprising that these channels are under tight control by a series of inhibitory extracellular ions, including zinc, magnesium, and H ϩ . We studied the inhibition by extracellular protons of recombinant NMDA receptor NR1/NR2B single-channel and macroscopic responses in transiently transfected human embryonic kidney HEK 293 cells using patch-clamp techniques. We report that proton inhibition proceeds identically in the absence or presence of agonist, which rules out the possibility that protonation inhibits receptors by altering coagonist binding. The response of macroscopic currents in excised patches to rapid jumps in pH was used to estimate the microscopic association and dissociation rates for protons, which were 1.4 ϫ 10 9 M Ϫ1 sec Ϫ1 and 110 -196 sec Ϫ1 , respectively (K d corresponds to pH 7.2). Protons reduce the open probability without altering the time course of desensitization or deactivation. Protons appear to slow at least one time constant describing the intra-activation shut-time histogram and modestly reduce channel open time, which we interpret to reflect a reduction in the overall channel activation rate and possible proton-induced termination of openings. This is consistent with a modest proton-dependent slowing of the macroscopic response rise time. From these data, we propose a physical model of proton inhibition that can describe macroscopic and single-channel properties of NMDA receptor function over a range of pH values.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protons Trap NR1/NR2B NMDA Receptors in a Nonconducting State

Banke¹,

Dravid²,

Traynelis³

2005

J. Neurosci.

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“…However, the nature of this residual response is not clear. If Zn 2ϩ inhibition of NR2A-containing receptors reflected enhancement of proton sensitivity, as has been reported for phenolethanolamines (30), the maximal Zn 2ϩ inhibition would depend on the concentration of protons. Based on the shift of proton curve in the presence of saturating Zn 2ϩ , the proton inhibition at neutral pH is still far from the maximal, resulting in a significant residual response.…”

Section: Mechanism Of the Voltage-independent Zn 2؉ Inhibition Of Nr1mentioning

confidence: 99%

Molecular determinants of coordinated proton and zinc inhibition of N- methyl- d -aspartate NR1/NR2A receptors

Low

Zheng

Lyuboslavsky

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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157

206

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Modulation of the N-methyl-D-aspartate (NMDA)-selective glutamate receptors by extracellular protons and Zn 2؉ may play important roles during ischemia in the brain and during seizures. Recombinant NR1͞ NR2A receptors exhibit a much higher apparent affinity for voltageindependent Zn 2؉ inhibition than receptors with other subunit combinations. Here, we show that the mechanism of this apparent high-affinity, voltage-independent Zn 2؉ inhibition for NR2A-containing receptors results from the enhancement of proton inhibition. We also show that the N-terminal leucine͞isoleucine͞valine binding protein (LIVBP)-like domain of the NR2A subunit contains critical determinants of the apparent high-affinity, voltage-independent Zn 2؉ inhibition. Mutations H42A, H44G, or H128A greatly increase the Zn 2؉ IC50 (by up to Ϸ700-fold) with no effect on the potencies of glutamate and glycine or on voltage-dependent block by Mg 2؉ . Furthermore, the amino acid residue substitution H128A, which mediates the largest effect on the apparent high-affinity Zn 2؉ inhibition among all histidine substitutions we tested, is also critical to the pH-dependency of Zn 2؉ inhibition. Our data revealed a unique interaction between two important extracellular modulators of NMDA receptors.G lutamate receptors are ligand-gated ion channels that mediate excitatory synaptic transmission in the central nervous system. Although overactivation of the N-methyl-D-aspartate (NMDA)-selective glutamate receptors can trigger neurodegeneration in neuropathological conditions such as stroke, NMDA receptor function is regulated under normal conditions by several extracellular ions (Mg 2ϩ , H ϩ , and Zn 2ϩ ), which exert strong tonic inhibition in a subunit selective manner (1). Inhibition by extracellular protons is particularly relevant for the neuropathological consequences of occlusive stroke because acidification of the extracellular environment during ischemia has been hypothesized to inhibit NMDA receptor overactivation by extrasynaptic glutamate that accumulates following metabolic failure (2, 3). The proton inhibition of NMDA receptors could delay their contribution to subsequent neuronal death until the pH gradients are restored, and this delay may provide a therapeutic window for postinsult treatment with NMDA receptor antagonists. Acidification of the extracellular space during electrographic seizure may also contribute to seizure termination through inhibition of NMDA receptor function (4, 5). Because of these potentially important aspects of the pH sensitivity of the NMDA receptor, we have sought to understand the structural basis by which the receptor might control its regulation by extracellular protons.In the central nervous system, the extracellular Zn 2ϩ concentration has been shown to vary under normal brain function as well as neuropathological conditions (6, 7). In addition, there are large amounts of chelatable Zn 2ϩ in the glutamatergic terminals of hippocampus (8-10), which are released in a Ca 2ϩ -dependent manner (for review, see ref. 6). ...

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“…A negative allosteric modulator (NAM) of the NR2B subtype of NMDA receptor, CP-101,606 Mott et al, 1998), also evidenced an antidepressant response in patients (Preskorn et al, 2008). Compounds of the NR2B NAM class bind at the interface of the NR2B/ NR1 amino terminal domains to allosterically reduce channel-opening probability to inhibit ion flux and functionally inhibit receptor activity (Karakas et al, 2011;Traynelis et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Differential Effects of an NR2B NAM and Ketamine on Synaptic Potentiation and Gamma Synchrony: Relevance to Rapid-Onset Antidepressant Efficacy

Nagy

Stoiljković

Menniti

et al. 2015

Neuropsychopharmacol

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Ketamine, a pan-NMDA receptor channel blocker, and CP-101,606, an NR2B-selective negative allosteric modulator, have antidepressant effects in humans that develop rapidly after the drugs are cleared from the body. It has been proposed that the antidepressant effect of ketamine results from delayed synaptic potentiation. To further investigate this hypothesis and potential mechanistic underpinnings we compared the effects of ketamine and CP-101,606 on neurophysiological biomarkers in rats immediately after drug administration and after the drugs had been eliminated. Local field and auditory-evoked potentials (AEPs) were recorded from primary auditory cortex and hippocampus in freely moving rats. Effects of different doses of ketamine or CP-101,606 were evaluated on amplitude of AEPs, auditory gating, and absolute power of delta and gamma oscillations 5-30 min (drug-on) and 5-6 h (drug-off) after systemic administration. Both ketamine and CP-101,606 significantly enhanced AEPs in cortex and hippocampus in the drug-off phase. In contrast, ketamine but not CP-101,606 disrupted auditory gating and increased gamma-band power during the drug-on period. Although both drugs affected delta power, these changes did not correlate with increase in AEPs in the drug-off phase. Our findings show that both ketamine and CP-101,606 augment AEPs after drug elimination, consistent with synaptic potentiation as a mechanism for antidepressant efficacy. However, these drugs had different acute effects on neurophysiological parameters. These results have implications for understanding the underlying mechanisms for the rapid-onset antidepressant effects of NMDA receptor inhibition and for the use of electrophysiological measures as translatable biomarkers.

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Phenylethanolamines inhibit NMDA receptors by enhancing proton inhibition

Cited by 205 publications

References 37 publications

Protons Trap NR1/NR2B NMDA Receptors in a Nonconducting State

Protons Trap NR1/NR2B NMDA Receptors in a Nonconducting State

Molecular determinants of coordinated proton and zinc inhibition of N- methyl- d -aspartate NR1/NR2A receptors

Differential Effects of an NR2B NAM and Ketamine on Synaptic Potentiation and Gamma Synchrony: Relevance to Rapid-Onset Antidepressant Efficacy

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