Structural Basis of the Proton Sensitivity of Human GluN1-GluN2A NMDA Receptors

Zhang, Jinbao; Chang, Shenghai; Xu, Pan; Miao, Miao; Wu, Haixiao; Zhang, Youyi; Zhang, Tongtong; Wang, Han; Zhang, Jilin; Xie, Chun; Song, Nan; Luo, Cheng; Zhang, Xing; Zhu, Shujia

doi:10.1016/j.celrep.2018.11.071

Cited by 53 publications

(49 citation statements)

References 55 publications

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“…Potentiation of N1/N2B NMDA receptors by Mg or polyamines involves relief of tonic inhibition by protons (Traynelis et al, 1995;Paoletti et al, 1995;Mony et al, 2011). Recent structural analysis (Jalali-Yazdi et al, 2018;Regan et al, 2018;Zhang et al, 2018) confirms earlier evidence (Gielen et al, 2009;Yuan et al, 2009) that conformational changes in the ATD and LBD underlie proton inhibition. In addition, however, mutations in the SY-TANLAAF motif of both N1 and N2 subunits also can alter the potency of proton inhibition (Low et al, 2003), highlighting the mechanistic link between agonist binding and the bundlecrossing gate (Ladislav et al, 2018;Wilding and Huettner, 2019).…”

Section: Acidic Ph Reduces CD Activationsupporting

confidence: 59%

Cadmium activates AMPA and NMDA receptors with M3 helix cysteine substitutions

Wilding

Huettner

2020

Journal of General Physiology

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AMPA and NMDA receptors are ligand-gated ion channels that depolarize postsynaptic neurons when activated by the neurotransmitter L-glutamate. Changes in the distribution and activity of these receptors underlie learning and memory, but excessive change is associated with an array of neurological disorders, including cognitive impairment, developmental delay, and epilepsy. All of the ionotropic glutamate receptors (iGluRs) exhibit similar tetrameric architecture, transmembrane topology, and basic framework for activation; conformational changes induced by extracellular agonist binding deform and splay open the inner helix bundle crossing that occludes ion flux through the channel. NMDA receptors require agonist binding to all four subunits, whereas AMPA and closely related kainate receptors can open with less than complete occupancy. In addition to conventional activation by agonist binding, we recently identified two locations along the inner helix of the GluK2 kainate receptor subunit where cysteine (Cys) substitution yields channels that are opened by exposure to cadmium ions, independent of agonist site occupancy. Here, we generate AMPA and NMDA receptor subunits with homologous Cys substitutions and demonstrate similar activation of the mutant receptors by Cd. Coexpression of the auxiliary subunit stargazin enhanced Cd potency for activation of Cys-substituted GluA1 and altered occlusion upon treatment with sulfhydryl-reactive MTS reagents. Mutant NMDA receptors displayed voltage-dependent Mg block of currents activated by agonist and/or Cd as well as asymmetry between Cd effects on Cys-substituted GluN1 versus GluN2 subunits. In addition, Cd activation of each Cys-substituted iGluR was inhibited by protons. These results, together with our earlier work on GluK2, reveal a novel mechanism shared among the three different iGluR subtypes for prying open the gate that controls ion entry into the pore.

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Section: Acidic Ph Reduces CD Activationsupporting

confidence: 59%

Cadmium activates AMPA and NMDA receptors with M3 helix cysteine substitutions

Wilding

Huettner

2020

Journal of General Physiology

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“…We have previously shown that these cells express NMDAR that mediates iCa 2+ rise through its release from IC pools, similar to findings from other groups, [8][9][10] along with mΔΨ depletion. Interestingly, given the relevance of pH for NMDAR channel function, [15][16][17] here we found that iCa 2+ rise is mainly elicited by acidic pH, rather than NMDA itself. However, and despite iCa 2+ responses were very similar between HBSS/pH6 and NMDA/ pH6, we unmasked that NMDA also activated cellular mechanisms that are evident only after a subsequent challenge with HBSS/pH6.…”

Section: Discussionmentioning

confidence: 55%

“…[11][12][13][14] Furthermore, the study of pH in NMDAR function is critical because it has been known for some time that the NMDAR is subject to proton inhibition because its proton sensor is tightly coupled with the ion channel gate, and the structural basis of this has been recently elucidated. [15][16][17] Moreover, the NMDA concentration used here has been found by us and others to regulate astrocyte and specific neuronal functions. 5,18,19 In our previous work, we also demonstrated that intracellular Ca 2+ (iCa 2+ ) rise was sensitive to competitive NMDAR inhibitors or GluN1 subunit Knock Down, demonstrating NMDAR involvement.…”

Section: Introductionmentioning

confidence: 67%

“…11,14 Moreover, under pathological conditions, more acidic pH values (≤5) can be reached in brain tissue, exposing the whole cell to an acidic environment. 12,28 More importantly, proton concentration has been found critical for NMDAR flux inhibition [15][16][17] and, 1mM NMDA has been previously found to regulate astrocyte and neuronal functions. 5,18,19 As shown in Figure 1A (left column), the maximal averaged response was observed with NMDA/pH6 (∫(ΔF/F 0 ) = 5.49) (The averaged response is that obtained averaging ΔF/F 0 responses from all experiments and cells tested in the same condition).…”

Section: Flux-independent Ica 2+ Response Is Elicited Mainly By Ph6mentioning

confidence: 99%

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NMDAR in cultured astrocytes: Flux‐independent pH sensor and flux‐dependent regulator of mitochondria and plasma membrane‐mitochondria bridging

et al. 2020

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Glutamate N-methyl-D-aspartate (NMDA) receptor (NMDAR) is critical for neurotransmission as a Ca 2+ channel. Nonetheless, flux-independent signaling has also been demonstrated. Astrocytes express NMDAR distinct from its neuronal counterpart, but cultured astrocytes have no electrophysiological response to NMDA. We recently demonstrated that in cultured astrocytes, NMDA at pH6 (NMDA/pH6) acting through the NMDAR elicits flux-independent Ca 2+ release from the Endoplasmic Reticulum (ER) and depletes mitochondrial membrane potential (mΔΨ). Here we show that Ca 2+ release is due to pH6 sensing by NMDAR, whereas mΔΨ depletion requires both: pH6 and flux-dependent NMDAR signaling. Plasma membrane (PM) NMDAR guard a non-random distribution relative to the ER and mitochondria. Also, NMDA/pH6 induces ER stress, endocytosis, PM electrical capacitance reduction, mitochondria-ER, and-nuclear contacts. Strikingly, it also produces the formation of PM invaginations near mitochondria along with structures referred to here as PM-mitochondrial bridges (PM-m-br). These and earlier data strongly suggest PM-mitochondria communication. As proof of the concept of mass transfer, we found that NMDA/pH6 provoked mitochondria labeling by the PM dye FM-4-64FX. NMDA/pH6 caused PM depolarization, cell acidification, and Ca 2+ release from most mitochondria. Finally, the MCU and microtubules were not involved in mΔΨ depletion, while actin cytoskeleton was partially involved. These findings demonstrate that NMDAR has concomitant flux-independent and flux-dependent actions in cultured astrocytes. K E Y W O R D S astrocyte, calcium, flux-independent, mitochondria, NMDAR, organelle communication | 16623 MONTES dE OCA BALdERAS ET AL.

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“…GluN2A NTD is also responsible for receptor structural changes in a closed conformation due to extracellular protonation (i.e., pH variations), which were shown to be independent of plasma membrane potential [44][45][46] and agonist binding [47]. This event was shown to be synergistically promoted by other NMDAR inhibitors, such as Zn 2+ [48]. Recently, R370W and P79R mutations of the GRIN2A (Glutamate Ionotropic Receptor NMDA Type Subunit 2A) gene, encoding for the GluN2A subunit, have been associated with augmented and reduced sensitivity to Zn 2+ , respectively [49].…”

Section: Nmdar Structure: Focus On the Glun2a Subunitmentioning

confidence: 98%

Synaptic GluN2A-Containing NMDA Receptors: From Physiology to Pathological Synaptic Plasticity

Franchini

Carrano

Luca

et al. 2020

IJMS

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N-Methyl-d-Aspartate Receptors (NMDARs) are ionotropic glutamate-gated receptors. NMDARs are tetramers composed by several homologous subunits of GluN1-, GluN2-, or GluN3-type, leading to the existence in the central nervous system of a high variety of receptor subtypes with different pharmacological and signaling properties. NMDAR subunit composition is strictly regulated during development and by activity-dependent synaptic plasticity. Given the differences between GluN2 regulatory subunits of NMDAR in several functions, here we will focus on the synaptic pool of NMDARs containing the GluN2A subunit, addressing its role in both physiology and pathological synaptic plasticity as well as the contribution in these events of different types of GluN2A-interacting proteins.

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Structural Basis of the Proton Sensitivity of Human GluN1-GluN2A NMDA Receptors

Cited by 53 publications

References 55 publications

Cadmium activates AMPA and NMDA receptors with M3 helix cysteine substitutions

Cadmium activates AMPA and NMDA receptors with M3 helix cysteine substitutions

NMDAR in cultured astrocytes: Flux‐independent pH sensor and flux‐dependent regulator of mitochondria and plasma membrane‐mitochondria bridging

Synaptic GluN2A-Containing NMDA Receptors: From Physiology to Pathological Synaptic Plasticity

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