Structure, function, and allosteric modulation of NMDA receptors

Hansen, Kasper B.; Yi, Feng; Perszyk, Riley E.; Furukawa, Hiro; Wollmuth, Lonnie P.; Gibb, Alasdair J.; Traynelis, Stephen F.

doi:10.1085/jgp.201812032

Cited by 432 publications

(475 citation statements)

References 337 publications

(607 reference statements)

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“…It is well known that the ionotropic function of the NMDAR is regulated by pH (1,2,(40)(41)(42)(43). However, this regulation has the opposite effect of what we observed here, acidic pH inhibits NMDAR flux, and indeed some of the responsible aa have been identified (41).…”

Section: Discussioncontrasting

confidence: 54%

“…The glutamate (Glu) N-methyl-D-aspartate (NMDA) receptor (NMDAR) is traditionally conceived as an ionotropic receptor with a critical role in neurotransmission. This function requires co-agonist (Gly or D-Ser) binding for channel opening and is regulated by ions (Mg2+, Zn2+, H+), or other molecules (1)(2)(3). The NMDAR is a tetramer of homodimers or a heterotrimer conformed by two obligate subunits GluN1 coupled to GluN2 and/or GluN3 subunits.…”

Section: Introductionmentioning

confidence: 99%

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Dual NMDAR signaling in astrocytes: flux-independent pH sensor & flux-dependent mitochondrial regulator through membrane-mitochondria communication

Balderas

Hernández‐Cruz

2019

Preprint

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Glutamate N-methyl-D-aspartate (NMDA) receptor (NMDAR) is critical for neurotransmission as a Ca2+ channel. Nonetheless, several reports have also demonstrated fluxindependent signaling. Astrocytes express NMDAR distinct from its neuronal counterpart, but cultured astrocytes have no electrophysiological response and controversial findings have questioned NMDAR function. We recently demonstrated that in cultured astrocytes NMDA at pH6 (NMDA/pH&) elicits flux-independent Ca2+ release from the Endoplasmic Reticulum (ER) and depletes mitochondrial membrane potential (m). Here we show that flux-independent Ca2+ release is mainly due to pH6, whereas m depletion requires both pH6 and flux-dependent NMDAR signaling. Immunofluorescence exhibited that plasma membrane (PM) NMDAR is apposed to ER and mitochondria or surrounds these organelles. Moreover, NMDA/pH6 treatment generated ER stress, increased endocytosis, mitochondria-ER and -nuclear contacts and strikingly, PM invaginations near mitochondria along with electrodense structures referred here as PMmitochondrial bridges (PM-m-br). These data and earlier observations strongly suggest PMmitochondria communication. As a proof of concept of this notion, NMDA/pH6 provoked mitochondria labeling by the PM dye FM-4-64FX. Finally, we analyzed by WB NMDAR subunit GluN1 to explore putative causes of NMDAR dual function, we found fragments with M.W. consistent with previously identified cleavage sites. Accordingly, GluN1 intracellular and extracellular domains presented little colocalization. Our findings demonstrate that NMDAR plays a dual function: a flux-independent pH sensor and a flux-dependent regulator of m. More importantly, m depletion seems to be mediated by PM-mitochondria communication. Finally, we found different GluN1 fragments that could be involved in NMDAR dual signaling, although causality awaits demonstration. NMDAR described so far, as it plays a central role for NMDAR assembly at the Endoplasmic Reticulum (ER) and its intracellular (IC) trafficking (1-3). However, NMDAR signaling is more complex, because Ca2+ inflow can switch on or off IC pathways with pro-survival or pro-death effects, suggested to be the result of synaptic or extra-synaptic NMDAR function, respectively (4). Moreover, several reports have also demonstrated flux-independent actions of this receptor (also termed metabotropic-like or non-canonical functions), that mediate long term depression (LTD) and other cellular events, through molecular mechanisms that have been only slightly investigated (5).In astrocytes, NMDAR expression and function were matter of debate for several years. However, nowadays it is clear that astrocytes in situ express functional NMDAR, although it displays several singularities, given in part by its subunit composition (6, 7). Nevertheless, classical electrophysiological experiments found no ionic flux in cultured astrocytes, and controversial findings have questioned NMDAR function (6,8). Nonetheless, we and others have recently demonstrated that the NMDAR ca...

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Section: Discussioncontrasting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Dual NMDAR signaling in astrocytes: flux-independent pH sensor & flux-dependent mitochondrial regulator through membrane-mitochondria communication

Balderas

Hernández‐Cruz

2019

Preprint

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“…Extracellular protons inhibit NMDA receptor function with an IC50 of ∼50 nM, corresponding to a pH of ∼7.3 (Traynelis & Cull-Candy, 1990; for review see Hansen et al, 2018). Proton inhibition proceeds identically in the absence or presence of agonist, which rules out the possibility that protonation inhibits receptors by altering co-agonist binding (Banke, Dravid, & Traynelis, 2005).…”

Section: Synaptic Ion Channels Modulated By Protonsmentioning

confidence: 99%

Synaptic signals mediated by protons and acid‐sensing ion channels

Uchitel

Inchauspe

Weissmann

2019

Synapse

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Extracellular pH changes may constitute significant signals for neuronal communication. During synaptic transmission, changes in pH in the synaptic cleft take place. Its role in the regulation of presynaptic Ca2+ currents through multivesicular release in ribbon‐type synapses is a proven phenomenon. In recent years, protons have been recognized as neurotransmitters that participate in neuronal communication in synapses of several regions of the CNS such as amygdala, nucleus accumbens, and brainstem. Protons are released by nerve stimulation and activate postsynaptic acid‐sensing ion channels (ASICs). Several types of ASIC channels are expressed in the peripheral and central nervous system. The influx of Ca2+ through some subtypes of ASICs, as a result of synaptic transmission, agrees with the participation of ASICs in synaptic plasticity. Pharmacological and genetical inhibition of ASIC1a results in alterations in learning, memory, and phenomena like fear and cocaine‐seeking behavior. The recognition of endogenous molecules, such as arachidonic acid, cytokines, histamine, spermine, lactate, and neuropeptides, capable of inhibiting or potentiating ASICs suggests the existence of mechanisms of synaptic modulation that have not yet been fully identified and that could be tuned by new emerging pharmacological compounds with potential therapeutic benefits.

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“…DNRAbs bind to both GluN2A and GluN2B subunits, with the epitope including a pentapeptide consensus sequence, DWEYS 10,11 . This antigenic target for DNRAbs is in the extracellularly located amino-terminal domain (ATD) of GluN2, an allosteric hub for modulating NMDAR function 21,22 . NMDARs containing GluN2A or GluN2B have distinct physiological, pharmacological, and signaling properties 22 .…”

Section: Introductionmentioning

confidence: 99%

“…This antigenic target for DNRAbs is in the extracellularly located amino-terminal domain (ATD) of GluN2, an allosteric hub for modulating NMDAR function 21,22 . NMDARs containing GluN2A or GluN2B have distinct physiological, pharmacological, and signaling properties 22 . Nevertheless, the contribution of the different GluN2 subunits to the SLE-associated neuropathologies is unclear.…”

Section: Introductionmentioning

confidence: 99%

Lupus auto-antibodies act as positive allosteric modulators at NMDA receptors and induce spatial memory deficits

Chan

Nestor

Huerta

et al. 2019

Preprint

Self Cite

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Patients with Systemic lupus erythematosus (SLE) experience various peripheral and central nervous system manifestations including spatial memory impairment. A subset of autoantibodies (DNRAbs) cross-react with the GluN2A and GluN2B subunits of the NMDA receptor (NMDAR). We find that these DNRAbs act as positive allosteric modulators on NMDARs with GluN2A-containing NMDARs, even those containing a single GluN2A subunit, exhibiting a much greater sensitivity to DNRAbs than those with exclusively GluN2B. Accordingly, GluN2A-specific antagonists provide greater protection from DNRAb-mediated neuronal cell death than GluN2B antagonists. Using transgenic mice to perturb expression of either GluN2A or GluN2B in vivo, we find that DNRAb-mediated disruption of spatial memory characterized by early neuronal cell death and subsequent microglia-dependent pathologies requires GluN2Acontaining NMDARs. Our results indicate that GluN2A-specific antagonists or negative allosteric modulators are strong candidates to treat SLE patients with nervous system dysfunction.

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Structure, function, and allosteric modulation of NMDA receptors

Abstract: Hansen et al. review recent structural data that have provided insight into the function and allosteric modulation of NMDA receptors.

Cited by 432 publications

References 337 publications

Dual NMDAR signaling in astrocytes: flux-independent pH sensor & flux-dependent mitochondrial regulator through membrane-mitochondria communication

Dual NMDAR signaling in astrocytes: flux-independent pH sensor & flux-dependent mitochondrial regulator through membrane-mitochondria communication

Synaptic signals mediated by protons and acid‐sensing ion channels

Lupus auto-antibodies act as positive allosteric modulators at NMDA receptors and induce spatial memory deficits

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