What is nmda

Professor Dennis Selkoe discusses the finding that amyloid beta seems to decrease the uptake of glutamate by synapses.

Professor Graham Collingridge describes the glutamate receptor, AMPA, the workhorse receptor for communicating information. Professor Seth Grant highlights PSD95 as an important example of a protein associated with a neurotransmitter receptor that affects learning.

What is NMDA? Download MP4. Related Content. ID: Source: G2C. The Neural Code Cognitive information is encoded in patterns of nervous activity and decoded by molecular listening devices at the synapse.

A major tenet of our proposal is that the NMDA receptor system becomes hypofunctional in either the normal brain or the AD brain after having first gone through an early stage of NRHyper. This hypothesis, consistent with the bulk of available data, assumes that the pattern of massive neurodegeneration in AD tends to follow the pattern of NFT formation, and that the neurons that display NFT at the time of autopsy are injured neurons that would be destined to slowly die and leave behind neurofibrillary debris.

However, this hypothesis also assumes that there is a less massive pattern of neuronal degeneration that corresponds to the pattern of amyloid deposition. Our hypothesis suggests that the neurodegenerative events in AD occur in two separate stages, by two separate mechanisms, and according to two separate patterns.

These have been difficult to tease apart because the two stages have a significant degree of temporal overlap and the two patterns have significant spatial overlap.

We propose that the first neurodegenerative stage entails the deposition of low concentrations of amyloid in the brain and interaction of amyloid with certain NMDA receptors in a manner that increases the sensitivity of these receptors to Glu so that the neurons bearing these receptors will be hyperstimulated and destroyed by endogenous Glu.

As these neurons degenerate, amyloid plaques may form and incorporate portions of the degenerating neurons and other neural and glial processes in the immediate environment. We postulate that it may not be a very conspicuous pattern of neuronal loss because it may be restricted to just the NMDA receptor-bearing neurons in our schematic circuit, that, control the release of transmitters onto the vulnerable pyramidal neuron Figure 1.

In stage I, the neurodegenerative process may produce few if any symptoms, because it. In addition, we postulate that, the recurrent collateral feedback loop Figure 1 remains relatively intact, so that, pyramidal neurons, as they begin to receive excessive stimulation, will be prevented from firing erratically onto other neurons and thereby prevented from generating florid symptoms.

The second stage commences when the loss of NMDA receptor-bearing neurons is sufficient, to substantially unleash the disinhibition syndrome in which many primary cerebrocortical and corticolimbic neurons are pathologically hyperstimulated through several signal transduction pathways at the same time.

At this point, psychosis and NRHypo-related cognitive disturbances could become evident. We propose that pyramidal neurons in many cortical and limbic brain regions will be affected, and will slowly degenerate and die as the stage II process progresses. Death and deletion of these neurons will disrupt mental functions just as excessive hyperactivation of these neurons will disrupt these functions. These second messenger systems are coupled to kinases or other possible factors relevant to protein phosphorylation; therefore, hyperactivation of these systems provides a rational explanation for NFT formation, which is believed to result from hyperphosphorylation of microtubule-associated proteins.

In stage II, neurodegeneration occurs as a network disturbance. The pattern of degeneration is determined by the pattern of connections within the network, and by the failure of inhibition over certain excitatory pathways within the network, causing specific cortical and limbic neurons innervated by these excitatory pathways to degenerate. This provides a rational explanation for the pattern of degeneration seen in AD.

National Center for Biotechnology Information , U. Journal List Dialogues Clin Neurosci v. Dialogues Clin Neurosci. John W. Nuri B. Farber , MD Nuri B. Olney , MD John W. Author information Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Abstract An increasing level of N-methyl-D-aspartate NMDA receptor hypofunction within the brain is associated with memory and learning impairments, with psychosis, and ultimately with excitotoxic brain injury.

NMDA glutamate receptors and memory Hippocampal long-term potentiation NMDA receptors are now understood to critically regulate a physiologic substrate for memory function in the brain.

Animal data Some studies of NMDA antagonist drug effects on in vivo hippocampal LTP induction have related synaptic changes to measures of memory and learning. Psychotomimetic effects of NMDA glutamate receptor antagonists In the s, the dissociative anesthetic, PCP, was observed to induce a psychotic state in human subjects. The NRHypo hypothesis Recent novel approaches to the treatment and prevention of drug-induced and idiopathic psychoses have emerged from the NMDA glutamate receptor hypofunction hypothesis.

Neurotoxic effects of NMDA glutamate receptor antagonists In order to better understand the mechanisms underlying the clinical effects of NMDA antagonist drugs and the clinical consequences of an NRHypo state, several research groups have begun examining the consequences of drug-induced NRHypo and have shown that one typical consequence is excessive release of Glu , and Ach , in the cerebral cortex.

Open in a separate window. Figure 1. This would create chaotic disruption among multiple intracellular second messenger systems, thereby causing derangement of cognitive functions subserved by the afflicted neurons, as well as eventual degeneration of these neurons. However, we hypothesize that a similar disinhibition mechanism and similar but not necessarily identical neural circuits and receptor mechanisms mediate damage induced in other corticolimbic brain regions by sustained NRHypo.

Treatment implications of NRHypo circuitry model The ability of certain classes of drugs to prevent the neurotoxic consequences of the NRHypo state in rat brain raises the question whether these drugs might also block the psychotomimetic consequences of the drug-induced NRHypo state in humans, or psychotic symptom formation in certain neuropsychiatrie disorders.

Age-related decreases in NMDA receptor function may explain age-related decreases in memory At least, four different laboratories studying three different nonhuman species mice, rats, and monkeys have reported that the NMDA receptor transmitter system becomes markedly hypofunctional with advancing age. Similarities between the neuronal degeneration seen in NRHypo and in AD There are important similarities between the overall pattern of NRHypo neurodegeneration and the pattern that has been described in the AD brain by various researchers.

Neurofibrillary tangles and psychosis could be associated through NRHypo We are beginning to study the possible relationship between this cytoskeletal disruption process in the NRHypo model and NFTs, its potential counterpart in the AD brain.

Amyloidopathy and NRHypo Most investigators of amyloidosis have tended to focus exclusively on the potential of beta-amyloid to kill neurons by itself without, reference to its potential pathological interaction with NMDA receptors. AD neurodegeneration: a two-stage process A major tenet of our proposal is that the NMDA receptor system becomes hypofunctional in either the normal brain or the AD brain after having first gone through an early stage of NRHyper.

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Bakker CB. Observations on the psychotomimetic effects of Sernyl. Compr Psychiatry. Cohen BD. Comparison of phencyclidine hydrochloride Sernyl with other drugs. Pandit SK. Br J Anaesth. Jansen KLR. Ketamine - can chronic use impair memory? Int J Addictions. Ellison G. The N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias. Hampton RY. Stereospecific binding of 3H-phencyclidine in brain membranes. Life Sci. Interestingly, intrareceptor allosteric interactions render the potency of glycine and d -serine at the GluN1 subunit sensitive to the identity of the GluN2 subunit Sheinin et al.

Multiple biophysical properties are also controlled by the GluN2 subunit. Furthermore, the probability that the channel will be open when all agonist-binding sites are occupied by agonists i.

The amino acid sequence of the intracellular CTD is highly variable among GluN2 subunits, thereby producing pronounced differences in interaction sites for phosphatases, kinases, and proteins responsible for anchoring at synaptic sites and surface trafficking Wenthold et al.

At least two different GluN2 subunits are expressed in most neurons, and thus virtually all neurons have the opportunity to signal through triheteromeric NMDA receptors that contain two GluN1 and two different GluN2 subunits Chazot et al. Many important properties of triheteromeric NMDA receptors in the CNS are still poorly understood, and the combinations of GluN2 subunits that can form triheteromeric receptors have not been fully established.

This knowledge gap persists because triheteromeric NMDA receptors have been difficult to study in isolation Chazot et al. That is, coexpression of GluN1 with two different GluN2 subunits e. A wealth of information exists describing the function, pharmacology, and regulation of recombinant diheteromeric NMDA receptors that contain two copies each of GluN1 and a single type of GluN2 e. Similarly, phosphorylation sites and trafficking properties of the intracellular GluN2 CTDs have been extensively studied in diheteromeric receptors, whereas the regulation of triheteromeric NMDA receptors that possess two distinct GluN2 CTDs remains elusive Tang et al.

Knowledge of the key NMDA receptor properties is an essential step to understand the roles of triheteromeric receptors in the brain. One recent advance that has enabled a determination of the functional and pharmacological properties of some triheteromeric NMDA receptors has been to control cell surface expression of receptors with known GluN2 subunit composition Hansen et al.

Importantly, these properties are not simply the average of the respective diheteromeric NMDA receptor properties. This new approach should allow new opportunities to develop therapeutic agents that target disease-relevant triheteromeric NMDA receptors Khatri et al. In iGluRs, the reentrant loop lines the intracellular portion of the ion channel pore, whereas elements of the third transmembrane segment M3 form the extracellular region of the pore. Among NMDA receptor subtypes, the residues in the pore region, which influence ion permeation, are highly conserved.

The ABDs form kidney-shaped bilobed structures that contain an upper lobe D1 and a lower lobe D2 with the agonist-binding site residing in the cleft between these two lobes Fig.

The ABD structure, intra- and intersubunit interactions, and its influence on receptor function have been studied for more than two decades. We will consider each of these domains in more detail below. Subsequent work by Gouaux and colleagues resulted in the first crystal structures of glutamate receptor ABDs Armstrong et al. The water-soluble ABD proteins produced by this approach retain ligand-binding activities comparable to those in full-length glutamate receptors, indicating that structural integrity and characteristics of the agonist-binding pocket are retained in isolated ABDs.

Multiple water molecules reside in close proximity to the agonists, and some form a hydrogen-bonding network that interacts with the ligand. The glycine-binding pocket in GluN1 is considerably smaller and more hydrophobic than the glutamate-binding pocket in GluN2 Furukawa and Gouaux, ; Furukawa et al. Residues within the glutamate-binding pocket that make atomic contacts with agonists or competitive antagonists are mostly conserved in the GluN2 subunits, and it has therefore proven difficult to identify ligands that bind to this site with strong selectivity between the different NMDA receptor subtypes.

However, recent crystallographic data have revealed the structural basis for binding of antagonists with modest selectivity Lind et al. Selectivity in these cases is driven by space outside the conventional binding pocket that competitive antagonists can exploit in a GluN2-dependent manner Fig. Consistently, mutations of Tyr in GluN1 alters deactivation time course of NMDA receptors, suggesting that the heterodimer interface can influence factors controlling deactivation, such as agonist dissociation or channel open time Furukawa et al.

This sensitivity appears to be mediated by a pair of conserved cysteine residues C and C within the GluN1 subunit Sullivan et al. Several other disulfide bonds exist in ABD crystal structures of both GluN1 and GluN2 subunits, but functional effects of their reduction or oxidation have not yet been described Takahashi et al.

Structures of the GluN1-GluN2A ABD heterodimer in complex with various agonists, partial agonists, and antagonists have suggested a structural basis for their modes of action Furukawa and Gouaux, ; Furukawa et al. This agonist-mediated ABD closure triggers formation of hydrogen bonds between residues from the upper and lower lobes, which are hypothesized to stabilize the agonist-bound ABD structure Kalbaugh et al. The energy provided by agonist binding and ABD closure triggers the receptor to undergo a series of conformational changes that ultimately open the ion channel pore.

Thus, ABD closure that results from agonist binding is the initial conformational change that ultimately triggers the process of ion channel gating. Binding of competitive antagonists, such as the glycine site antagonist DCKA and the glutamate site antagonist D-AP5, stabilizes an open cleft conformation that is incapable of triggering channel gating Fig. However, one notable difference exists. However, these crystal structures capture only one conformation of the isolated ABDs, which may be influenced by the lack of interacting domains ATD and TMD and is further stabilized by contacts in the crystal lattice.

These studies suggest that the ABDs fluctuate between open and closed cleft conformations even in the absence of agonist i. However, binding of full agonist changes the energy landscape for ABD conformations to strongly favor a fully closed conformation, whereas binding of partial agonists is less efficient in changing this landscape, thereby enabling the ABD to adopt conformations with intermediate domain closure more frequently than full agonists.

Hence, a conformational selection mechanism is likely to account for partial agonism in NMDA receptors despite the lack of crystallographic data showing intermediate domain closure for partial agonists. Second, the TMDs have a quasi-fourfold symmetry, whereas the extracellular portion shows twofold symmetry between the two ABD heterodimers and ATD heterodimers in a dimer-of-dimer arrangement.

Thus, there is a symmetry mismatch between the TMD layer and the extracellular layers of the receptor. These contacts may provide the structural basis of the GluN2 subunit dependence of glycine potency.

The structure of the NMDA receptor thus reveals unique intra- and interdomain contacts that provide a framework for understanding allosteric interactions between subunits, as well as allosteric modulation by small-molecule ligands. Although the crystallographic structures of intact NMDA receptors advance our understanding of the structure—function relationship, they nevertheless capture only a low energy conformation among the many conformations that the NMDA receptor moves through en route to activation.

The structures represent the agonist-bound, inhibited receptor with the ion channel closed. However, recent cryo-EM data have described multiple conformations in the extracellular region, providing the first dynamic pictures of NMDA receptor conformational changes and insight into the structural mechanism of receptor activation and allosteric modulation Tajima et al.

Unfortunately, the TMDs for the active and antagonist-bound states are not well resolved in the cryo-EM structures, limiting mechanistic insights into gating and antagonism. This tension can lead to reorientation of the M3 helix in AMPA receptors as well as a kink at an alanine residue that appears to serve as a hinge.

This arrangement, which is revealed in crystal and cryo-EM structures of intact iGluRs, is characterized by a protein—protein interface formed by the upper R2 lobes from the GluN1 and GluN2 subunits, whereas the lower R1 lobes, which connect to the ABDs, are almost completely separated.

These crystal structures revealed that only one residue in this modulatory site is different between GluN2A and GluN2B subunits, but sensitivity to ifenprodil is not introduced by converting this or other residues in GluN2A to that in GluN2B Karakas et al. For this reason, allosteric modulation of NMDA receptors by the ATD is intensely investigated, and drug discovery studies are poised to identify novel ATD ligands with therapeutic potential. All three transmembrane helices M1, M3, and M4 and the membrane-reentrant pore-forming loop M2 are involved in the process of pore opening i.

The transmembrane helix M3 forms a helical bundle crossing that physically occludes the pore, and thus M3 helices must change their position before ions can pass through the channel pore Jones et al.

Multiple structural and functional studies suggest that these residues comprise the activation gate and that dilation of the M3 helical bundle crossing is thought to be the key change that allows ion conduction Beck et al.

What sequence of events leads to M3 rearrangement? Agonist binding to the bilobed ABDs involves a clamshell closure around the ligands that must be the first step in a sequence of conformational changes that lead to gating. These are followed by multiple short-lived, intermediate conformations that precede a rapid transition from the closed to the open state of the ion channel, inferred by brief, kinetically distinguishable closed states in the single-channel record and the relatively slow time course for receptor activation by supersaturating agonist Banke and Traynelis, ; Popescu et al.

However, there is poor understanding of the protein conformations that represent the rate limiting steps en route to channel opening. Moreover, the lifetimes of some of these intermediate conformations are brief, suggesting they are unlikely to be captured in crystal structures or cryo-EM studies, leaving functional experiments as the most feasible yet imperfect way to glean clues as to how these changes might control channel opening.

Recent functional studies have built explicit models of channel activation in which specific conformations are hypothesized for each of the four subunits Gibb et al. Moreover, work with disease-causing mutations identified in human patients has provided key insights into the elements that comprise the gating control mechanism. Moreover, the different amino acid sequences for pre-M1 and pre-M4 that exist for GluN1 and GluN2 as well as different positions of these elements in relation to the gating ring could lead to distinct lifetimes for intermediate conformations that must be traversed before rapid pore dilation Erreger et al.

The sequence of protein conformational changes that trigger channel gating can be described as reaction schemes i. The first widely applied kinetic model for NMDA receptor gating was solely designed to account for the time course of the macroscopic current response and consisted of two identical but independent glutamate binding steps, one desensitized state, one closed state, and one open state Lester and Jahr, This simple kinetic model appeared to effectively capture key features of macroscopic NMDA receptor responses but was not intended to describe the complexity observed in single-channel recordings Ascher et al.

Furthermore, the usefulness of the Lester and Jahr model was limited by the lack of glycine-binding steps required for receptor activation. Kinetic models that account for both glutamate- and glycine-binding steps as well as intersubunit interactions between the glutamate and glycine ABDs have also been developed Benveniste et al.

Newer, more complex kinetic models have been proposed that better describe single-channel data by incorporating multiple steps between binding and gating Banke and Traynelis, ; Popescu et al. Investigations of macroscopic and single-channel responses to partial and full agonists suggest that agonist binding to either GluN1 or GluN2 controls distinct steps in the kinetic model Banke and Traynelis, ; Auerbach and Zhou, ; Erreger et al.

In some of these models, the actions of allosteric modulators are accounted for by explicitly representing the modulator bound and unbound receptor as independent states Banke et al. Other models for channel blockers and other use-dependent modulators have been described that exclusively allow modulators to bind to the open state Huettner and Bean, ; MacDonald et al. Some kinetic models suggest that such subunit-specific conformational changes are required in all four NMDA receptor subunits to trigger channel gating and that these structural changes can occur in any order to arrive at an intermediate state that can subsequently transition to the open state of the ion channel Banke and Traynelis, ; Auerbach and Zhou, ; Erreger et al.

Other models account for macroscopic and single-channel responses by including a few sequential gating steps in a linear kinetic model with an implicit order for slow and fast gating steps Popescu et al. These models have been used to explore the kinetic aspects of modal gating Zhang et al. Although the mechanism remains elusive, mode switching has been proposed to influence the time course of the synaptic current Zhang et al.

All these kinetic models for NMDA receptor gating that faithfully describe both macroscopic responses and single-channel data require both multiple pregating steps and multiple open states. The interpretation of this observation is that ion channel opening in NMDA receptors is not directly coupled to agonist-induced ABD closure; instead, the receptor must proceed through a sequence of conformational changes that couple agonist binding to ion channel gating.

The ion channel pore in NMDA receptors can be divided into the intracellular and extracellular vestibules separated by a narrow constriction Fig. The narrow restriction resides approximately halfway across the membrane at the apex of the membrane reentrant loop M2 i. Functional data therefore suggest a structural asymmetry, where the apexes of M2 in GluN1 and GluN2 are slightly staggered Sobolevsky et al. Recent data describing the pore of the AMPA receptor in the open state reinforce the idea that the apex of the reentrant loops form a constriction that impacts ion permeation Twomey et al.

The structural basis for this functional asymmetry will require high-resolution images of the NMDA receptor in the open state. This channel block is highly dependent on the membrane potential i. The NMDA receptor ion channel pore can be blocked in a voltage-dependent manner by a wide range of organic cations with diverse chemical structures Huettner and Bean, ; Brackley et al. These compounds almost exclusively block open channels in activated NMDA receptors and are positively charged at physiological pH, a mechanism of channel block termed uncompetitive or use dependent.

Some channel blockers have also been shown to facilitate channel closure, presumably by interacting with the channel gate Blanpied et al. Channel blockers proposed to have bifunctionality include nitromemantine derivatives that bind the ion channel pore, facilitating the targeting of a nitro group to a redox-mediated regulatory site on the receptor Takahashi et al.

In general, the open channel blockers are considered nonselective among NMDA receptor subtypes Dravid et al. NMDA receptor channel blockers have robust neuroprotective effects in animal models of CNS disorders that involve excessive NMDA receptor activation, such as stroke, epilepsy, and traumatic brain injury. However, clinical trials have not been successful because of dose-limiting side effects, patient heterogeneity, and a narrow temporal window for intervention that could have confounded interpretation Ikonomidou and Turski, ; Farin and Marshall, ; Muir, ; see also Table S2 in Yuan et al.

NMDA receptor channel blockers that bind with high affinity, such as ketamine and PCP, are typically dissociative anesthetics, and their clinical use is limited by psychomimetic side effects. Nonetheless, there is an intense interest in use of ketamine or similar molecules for the treatment of major depressive disorder because of several promising clinical trials in recent years based on the discovery of antidepressant effects for NMDA receptor antagonists Niciu et al.

Interestingly, Glasgow et al. Thus, the affinity of these blockers for their binding site in the channel may be allosterically affected by the conformational changes in the receptor protein associated with desensitization.

NMDA receptors are complex macromolecular membrane-bound protein complexes, and their functional properties and membrane trafficking can be altered by extracellular ions, phosphorylation, and intracellular binding proteins. Additionally, the differences between various diheteromeric and triheteromeric NMDA receptor subtypes create selective actions of many of these types of modulation. Here, we will describe various forms of endogenous regulation of NMDA receptor function. Thus, neuronal NMDA receptors are tonically inhibited by protons at physiological pH and are therefore poised to respond to small changes in extracellular pH that can occur under physiological conditions caused by release of protons from acidic synaptic vesicles or movement of protons across the plasma membrane by pumps Chesler, Furthermore, pathological conditions, including seizure and ischemia, produce extracellular acidification, which can decrease pH to levels that strongly inhibit NMDA receptor function Chesler, Proton inhibition is voltage independent, and without effect on glutamate potency; low pH produces modest shifts in the glycine potency Tang et al.

The structural determinants underlying proton inhibition are unknown, although mutations at the ABD interface, linkers to pore-forming elements, and within the M2 reentrant loop can all influence pH sensitivity Low et al. This suggests that NMDA receptor gating is tightly coupled to proton inhibition of the receptor. This idea is consistent with the observation that channel blockers appear to sense the protonation state of the receptor Dravid et al.

The actions of ATD modulators appear to involve a change in the pKa of the proton sensor that leads to enhancement or reduction of tonic proton inhibition at physiological pH. In contrast, the binding of extracellular polyamines reduces the sensitivity to extracellular pH, resulting in potentiation due to reduced tonic inhibition by physiological levels of protons Traynelis et al. Several endogenous neurosteroids positively and negatively modulate NMDA receptor activity Traynelis et al.

For instance, pregnenolone sulfate has dual actions on NMDA receptor responses, having both inhibitory and potentiating activity over a wide range of potencies Horak et al. The potentiating actions of pregnenolone sulfate are most prominent when applied before receptor activation, whereas inhibitory actions arise when applied continuously Horak et al. Other neurosteroid analogues, such as pregnanolone sulfate, inhibit all NMDA receptor subtypes i.

For GluN2A, pregnanolone sulfate has been proposed to increase the occupancy of a desensitized state Kussius et al. In contrast, 24 S -hydroxycholesterol and related analogues appear to be pan-potentiators, whereas 25 S -hydroxycholesterol may antagonize actions of endogenous 24 S -hydroxycholesterol Paul et al.

Some of these neurosteroids and analogues have been shown to exhibit agonist dependency, although this property is difficult to assess, because neurosteroids can have distinct actions on NMDA receptors, dependent on the timing of modulator application i.

Additionally, steroid derivatives may partition into the membrane en route to their active site, which will alter the concentration—response relationship of their actions Borovska et al.

A recent study reported that cholesterol modulates NMDA receptor function and its removal inhibited receptor activity Korinek et al. Although a clear binding site has not been resolved, it seems likely that neurosteroid derivatives interact directly with the receptor rather than simply alter membrane fluidity. A subset of neurosteroid inhibitors also have voltage-dependent actions, suggesting that they may inhibit NMDA receptors through blocking the channel Vyklicky et al.

These findings highlight the complexity associated with neurosteroid activity, and more work is required to delineate the mechanism of action of these compounds.

The process of desensitization is broadly defined as a decrease in a response in the continued presence of a stimulus. Most ligand-gated channels can desensitize in the continued presence of agonist by a mechanism thought to involve a conformational change to a stable and long-lived agonist-bound closed state.

However, this desensitization is sensitive to intracellular dialysis, being more prominent in excised outside-out membrane patches Sather et al. Glycine-dependent NMDA receptor desensitization is present only in subsaturating glycine concentrations Mayer et al. Thus, when glutamate binds to GluN2 in the absence of high concentrations of glycine, the current will initially rise to a peak and then decline to a new equilibrium as glycine unbinds from the receptor after the allosteric reduction in glycine affinity.

Recent structural data for NMDA receptors provide plausible models for the negative allosteric coupling between glutamate- and glycine-binding sites, given their close proximity Karakas and Furukawa, ; Lee et al. However, the structural features that enable glycine-dependent desensitization remain poorly understood. Recent discoveries from genetic analyses that link NMDA receptors to specific disease conditions, the emerging evidence of the antidepressant effects of NMDA receptor antagonists, and accelerating identification of new subunit-selective modulators have reinvigorated the long-standing interest in NMDA receptors as therapeutic targets.

The field now seems poised to achieve new levels of understanding of the functional roles of NMDA receptors in physiology and disease. The rapidly increasing volume of crystallographic and cryo-EM data has created an opportunity to view function through structure, which will inevitably improve our insight to the mechanisms by which agonist binding is linked to channel gating and how different NMDA receptor subunits contribute to the conformational changes that occur during gating and allosteric modulation.