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måndag 16 december 2019

HAKU: PSD-95 (AND) NMDAr

See Gene information for nmdar psd95

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1.
Experience-dependent development of visual sensitivity in larval zebrafish.
Xie J, Jusuf PR, Bui BV, Goodbourn PT.
Sci Rep. 2019 Dec 12;9(1):18931. doi: 10.1038/s41598-019-54958-6.
PMID:
31831839
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2.
PDZ/PDZ interaction between PSD-95 and nNOS neuronal proteins: A thermodynamic analysis of the PSD95-PDZ2/nNOS-PDZ interaction.
Murciano-Calles J, Coello A, Cámara-Artigas A, Martinez JC.
J Mol Recognit. 2019 Nov 19:e2826. doi: 10.1002/jmr.2826. [Epub ahead of print]
N-Methyl-D-aspartate (NMDA) receptors are key components in synaptic communication and are highly relevant in central nervous disorders, where they trigger excessive calcium entry into the neuronal cells causing harmful overproduction of nitric oxide by the neuronal nitric oxide synthase (nNOS) protein. Remarkably, NMDA receptor activation is aided by a second protein, postsynaptic density of 95 kDa (PSD95), forming the ternary protein complex NMDA/PSD95/nNOS. To minimize the potential side effects derived from blocking this ternary complex or either of its protein components, a promising approach points to the disruption of the PSD-95/nNOS interaction which is mediated by a PDZ/PDZ domain complex. Since the rational development of molecules targeting such protein-protein interaction relies on energetic and structural information herein, we include a thermodynamic and structural analysis of the PSD95-PDZ2/nNOS-PDZ. Two energetically relevant events are structurally linked to a "two-faced" or two areas of recognition between both domains. First, the assembly of a four-stranded antiparallel β-sheet between the β hairpins of nNOS and of PSD95-PDZ2, mainly enthalpic in nature, contributes 80% to the affinity. Second, binding is entropically reinforced by the hydrophobic interaction between side chains of the same nNOS β-hairpin with the side chains of α2-helix at the binding site of PSD95-PDZ2, contributing the remaining 20% of the total affinity. These results suggest strategies for the future rational design of molecules able to disrupt this complex and constitute the first exhaustive thermodynamic analysis of a PDZ/PDZ interaction.
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3.
Linking NMDA Receptor Synaptic Retention to Synaptic Plasticity and Cognition.
Franchini L, Stanic J, Ponzoni L, Mellone M, Carrano N, Musardo S, Zianni E, Olivero G, Marcello E, Pittaluga A, Sala M, Bellone C, Racca C, Di Luca M, Gardoni F.
iScience. 2019 Sep 27;19:927-939. doi: 10.1016/j.isci.2019.08.036. Epub 2019 Aug 27.
PMID:
31518901
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4.
NMDA receptor modulation of glutamate release in activated neutrophils.
Del Arroyo AG, Hadjihambi A, Sanchez J, Turovsky E, Kasymov V, Cain D, Nightingale TD, Lambden S, Grant SGN, Gourine AV, Ackland GL.
EBioMedicine. 2019 Sep;47:457-469. doi: 10.1016/j.ebiom.2019.08.004. Epub 2019 Aug 8.
NMDA receptor (NMDAR) subunit composition plays a pivotal role in synaptic plasticity at excitatory synapses. Still, the mechanisms responsible for the synaptic retention of NMDARs following induction of plasticity need to be fully elucidated. Rabphilin3A (Rph3A) is involved in the stabilization of NMDARs at synapses through the formation of a complex with GluN2A and PSD-95. Here we used different protocols to induce synaptic plasticity in the presence or absence of agents modulating Rph3A function. The use of Forskolin/Rolipram/Picrotoxin cocktail to induce chemical LTP led to synaptic accumulation of Rph3A and formation of synaptic GluN2A/Rph3A complex. Notably, Rph3A silencing or use of peptides interfering with the GluN2A/Rph3A complex blocked LTP induction. Moreover, in vivo disruption of GluN2A/Rph3A complex led to a profound alteration of spatial memory. Overall, our results demonstrate a molecular mechanism needed for NMDAR stabilization at synapses after plasticity induction and to trigger downstream signaling events necessary for cognitive behavior.Free PMC Article
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5.
NYX-2925 induces metabotropic N-methyl-d-aspartate receptor (NMDAR) signaling that enhances synaptic NMDAR and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor.
Bowers MS, Cacheaux LP, Sahu SU, Schmidt ME, Sennello JA, Leaderbrand K, Khan MA, Kroes RA, Moskal JR.
J Neurochem. 2019 Aug 3. doi: 10.1111/jnc.14845. [Epub ahead of print]
PMID:
31376158
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6.
A primate-specific short GluN2A-NMDA receptor isoform is expressed in the human brain.
Warming H, Pegasiou CM, Pitera AP, Kariis H, Houghton SD, Kurbatskaya K, Ahmed A, Grundy P, Vajramani G, Bulters D, Altafaj X, Deinhardt K, Vargas-Caballero M.
Mol Brain. 2019 Jul 4;12(1):64. doi: 10.1186/s13041-019-0485-9.
Glutamate receptors of the N-methyl-D-aspartate (NMDA) family are coincident detectors of pre- and postsynaptic activity, allowing Ca2+ influx into neurons. These properties are central to neurological disease mechanisms and are proposed to be the basis of associative learning and memory. In addition to the well-characterised canonical GluN2A NMDAR isoform, large-scale open reading frames in human tissues had suggested the expression of a primate-specific short GluN2A isoform referred to as GluN2A-S. Here, we confirm the expression of both GluN2A transcripts in human and primate but not rodent brain tissue, and show that they are translated to two corresponding GluN2A proteins present in human brain. Furthermore, we demonstrate that recombinant GluN2A-S co-assembles with the obligatory NMDAR subunit GluN1 to form functional NMDA receptors. These findings suggest a more complex NMDAR repertoire in human brain than previously thought.
Introduction
NMDA receptors are activated by coincident glutamate binding and intracellular depolarisation. Ca2+ entry via NMDARs can gate long-term biochemical and gene expression changes that alter synaptic strength, which are proposed as central to mechanisms of memory storage [17] and neurodegenerative processes [9]. Our current knowledge of NMDAR function is largely derived from the study of rodent receptors and heterologous expression of cloned rodent genes. Tetrameric NMDARs comprise two obligatory GluN1 subunits and two GluN2 or GluN3 subunits, and in the adult forebrain GluN1/GluN2A, GluN1/GluN2B diheteromers, and GluN1/GluN2A/GluN2B triheteromers are the most common [18, 19]. The subunit combination confers the distinct biophysical and pharmacological properties to the receptor channel. The developmentally and anatomically regulated gene expression of NMDAR subunits, together with diverse post-translational modification mechanisms and protein interactions, determines the assembly, trafficking, synaptic or extrasynaptic localisation and internalisation of NMDARs (Reviewed in [16]) and their correct functioning is necessary for human brain functions [5, 6, 21].
Homologous rodent and human NMDARs do share highly conserved subunit sequences and exhibit almost identical pharmacological properties [10]. However, large scale open reading frame studies performed with mRNA from a mix of human tissues [20, 28] have suggested that in addition to the conserved NMDAR canonical isoform of GluN2A in chordates, a shorter isoform is produced in humans (GluN2A-S) generated by alternative splicing of human GRIN2A (Fig. 1a). Here, we show that this alternative NMDAR isoform is expressed in the human and primate brain, and that it forms functional receptors together with the obligatory subunit GluN1 [15]. The presence of alternative NMDAR subunits not expressed in rodent model systems indicates the existence of unexplored neural mechanisms in human synapses with relevance to normal function, ageing and neurological disease....
Here we describe for the first time the brain expression of an uncharacterised, primate-specific NMDAR subunit. The splice site for GluN2A-S suggests that it will contain a diverging 19 aa sequence in its extreme C-terminal domain (Fig. 2a), in addition to lacking the distal carboxy terminal domain (183 amino acids) that contains PKC/SFK phosphorylation sites, two PDZ binding motifs that allow synaptic localisation [4, 12, 14], and a dileucin clathrin adaptor motif involved in receptor internalisation [13]. Following many lines of published evidence, these differences suggest that the dynamic regulation of GluN2A-S in response to stimuli could diverge from GluN2A subunit-containing NMDARs. This could impact the number of receptors present synaptically or extrasynaptically, the insertion of new receptors into the membrane, their lateral diffusion and clustering into synapses and their active removal. The potential changes in human synapses compared to mouse neurons void of GluN2A-S could result in distinct mechanisms involved in activity-dependent plasticity of synapses, which will highly depend upon its triheteromeric partners [1, 8, 19].
...Together, our data suggest that GluN2A-S is a primate-specific NMDAR subunit and a substantial component of functional NMDARs in the adult human brain. Many neuronal mechanisms discovered in mice have been successfully recapitulated in humans. However, mounting evidence suggests that there are important differences between rodent and human neurons that result in distinct signal integration properties [22, 23, 26] and proteomic composition of synapses [3]. Species differences may ultimately impact the way in which human neural circuits can be computationally modelled [7], and the translation of pre-clinical findings into approved therapies [24]. Further analyses of GluN2A-S spatio-temporal gene expression and synaptic/ extrasynaptic localisation will enhance our knowledge of their functional role and may uncover NMDAR trafficking mechanisms present only in primates and diverging sequences may uncover novel therapeutic targets.
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  1. 4. Ref.
    Cousins SL, Kenny AV, Stephenson FA. Delineation of additional PSD-95 binding domains within NMDA receptor NR2 subunits reveals differences between NR2A/PSD-95 and NR2B/PSD-95 association. Neuroscience. 2009;158:89–95.

 
7.
PSD-95 deficiency disrupts PFC-associated function and behavior during neurodevelopment.
Coley AA, Gao WJ.
Sci Rep. 2019 Jul 1;9(1):9486. doi: 10.1038/s41598-019-45971-w.
PMID:
31263190
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8.
Preso regulates NMDA receptor-mediated excitotoxicity via modulating nitric oxide and calcium responses after traumatic brain injury.
Luo P, Li X, Wu X, Dai S, Yang Y, Xu H, Jing D, Rao W, Xu H, Gao X, Fei Z, Lu H.
Cell Death Dis. 2019 Jun 24;10(7):496. doi: 10.1038/s41419-019-1731-x.
PMID:
31235685
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9.
IQSEC2-Associated Intellectual Disability and Autism.
Levy NS, Umanah GKE, Rogers EJ, Jada R, Lache O, Levy AP.
Int J Mol Sci. 2019 Jun 21;20(12). pii: E3038. doi: 10.3390/ijms20123038. Review.
PMID:
31234416
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10.
NGL-3 in the regulation of brain development, Akt/GSK3b signaling, long-term depression, and locomotive and cognitive behaviors.
Lee H, Shin W, Kim K, Lee S, Lee EJ, Kim J, Kweon H, Lee E, Park H, Kang M, Yang E, Kim H, Kim E.
PLoS Biol. 2019 Jun 5;17(6):e2005326. doi: 10.1371/journal.pbio.2005326. eCollection 2019 Jun.
PMID:
31166939
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11.
Bisphenol-A induces neurodegeneration through disturbance of intracellular calcium homeostasis in human embryonic stem cells-derived cortical neurons.
Wang H, Zhao P, Huang Q, Chi Y, Dong S, Fan J.
Chemosphere. 2019 Aug;229:618-630. doi: 10.1016/j.chemosphere.2019.04.099. Epub 2019 Apr 15.
PMID:
31102917
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12.
Contributions of Mass Spectrometry to the Identification of Low Molecular Weight Molecules Able to Reduce the Toxicity of Amyloid-β Peptide to Cell Cultures and Transgenic Mouse Models of Alzheimer's Disease.
Ştefănescu R, Stanciu GD, Luca A, Caba IC, Tamba BI, Mihai CT.
Molecules. 2019 Mar 24;24(6). pii: E1167. doi: 10.3390/molecules24061167. Review.
PMID:
30909659
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13.
An Assay to Determine Mechanisms of Rapid Autoantibody-Induced Neurotransmitter Receptor Endocytosis and Vesicular Trafficking in Autoimmune Encephalitis.
Amedonu E, Brenker C, Barman S, Schreiber JA, Becker S, Peischard S, Strutz-Seebohm N, Strippel C, Dik A, Hartung HP, Budde T, Wiendl H, Strünker T, Wünsch B, Goebels N, Meuth SG, Seebohm G, Melzer N.
Front Neurol. 2019 Mar 1;10:178. doi: 10.3389/fneur.2019.00178. eCollection 2019.
PMID:
30881339
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14.
Role of Palmitoylation of Postsynaptic Proteins in Promoting Synaptic Plasticity.
Matt L, Kim K, Chowdhury D, Hell JW.
Front Mol Neurosci. 2019 Jan 31;12:8. doi: 10.3389/fnmol.2019.00008. eCollection 2019. Review.
Many postsynaptic proteins undergo palmitoylation, the reversible attachment of the fatty acid palmitate to cysteine residues, which influences trafficking, localization, and protein interaction dynamics. Both palmitoylation by palmitoyl acyl transferases (PAT) and depalmitoylation by palmitoyl-protein thioesterases (PPT) is regulated in an activity-dependent, localized fashion. Recently, palmitoylation has received attention for its pivotal contribution to various forms of synaptic plasticity, the dynamic modulation of synaptic strength in response to neuronal activity. For instance, palmitoylation and depalmitoylation of the central postsynaptic scaffold protein postsynaptic density-95 (PSD-95) is important for synaptic plasticity. Here, we provide a comprehensive review of studies linking palmitoylation of postsynaptic proteins to synaptic plasticity.Free PMC Article
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15.
A Role for Postsynaptic Density 95 and Its Binding Partners in Models of Traumatic Brain Injury.
Patel MV, Sewell E, Dickson S, Kim H, Meaney DF, Firestein BL.
J Neurotrauma. 2019 Jul 1;36(13):2129-2138. doi: 10.1089/neu.2018.6291. Epub 2019 Mar 28.
PMID:
30747034
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16.
Higher Levels of Protein Palmitoylation in the Frontal Cortex across Aging Were Associated with Reference Memory and Executive Function Declines.
Zamzow DR, Elias V, Acosta VA, Escobedo E, Magnusson KR.
eNeuro. 2019 Feb 7;6(1). pii: ENEURO.0310-18.2019. doi: 10.1523/ENEURO.0310-18.2019. eCollection 2019 Jan-Feb.
Cognitive decline with aging is often due to altered levels of protein expression. The NMDA receptor (NMDAR) and the complex of proteins surrounding the receptor are susceptible to age-related changes in expression. In the frontal cortex of aged mice, there is a significant loss of expression of the GluN2B subunit of the NMDAR, an increase in Fyn expression, and no change in PSD-95. Studies have also found that, in the frontal cortex, phosphorylation of GluN2B subunits and palmitoylation of GluN2 subunits and NMDAR complex proteins are affected by age. In this study, we examined some of the factors that may lead to the differences in the palmitoylation levels of NMDAR complex proteins in the frontal cortex of aged animals. The Morris water maze was used to test spatial learning in 3- and 24-month-old mice. The acyl-biotinyl exchange method was used to precipitate palmitoylated proteins from the frontal cortices and hippocampi of the mice. Additionally, brain lysates from old and young mice were probed for the expression of fatty acid transporter proteins. An age-related increase of palmitoylated GluN2A, GluN2B, Fyn, PSD-95, and APT1 (acyl protein thioesterase 1) in the frontal cortex was associated with poorer reference memory and/or executive functions. These data suggest that there may be a perturbation in the palmitoylation cycle in the frontal cortex of aged mice that contributes to age-related cognitive declines.Free PMC Article
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17.
Involvement of the synapse-specific zinc transporter ZnT3 in cadmium-induced hippocampal neurotoxicity.
Ben Mimouna S, Le Charpentier T, Lebon S, Van Steenwinckel J, Messaoudi I, Gressens P.
J Cell Physiol. 2019 Feb 4. doi: 10.1002/jcp.28245. [Epub ahead of print]
The present study examined the involvement of zinc (Zn)-transporters (ZnT3) in cadmium (Cd)-induced alterations of Zn homeostasis in rat hippocampal neurons. We treated primary rat hippocampal neurons for 24 or 48 hr with various concentrations of CdCl2 (0, 0.5, 5, 10, 25, or 50 μM) and/or ZnCl 2 (0, 10, 30, 50, 70, or 90 μM), using normal neuronal medium as control. By The CellTiter 96 ® Aqueous One Solution Cell Proliferation Assay (MTS; Promega, Madison, WI) assay and immunohistochemistry for cell death markers, 10 and 25 μM of Cd were found to be noncytotoxic doses, and both 30 and 90 μM of Zn as the best concentrations for cell proliferation. We tested these selected doses. Cd, at concentrations of 10 or 25 μM (and depending on the absence or presence of Zn), decreased the percentage of surviving cells. Cd-induced neuronal death was either apoptotic or necrotic depending on dose, as indicated by 7-AAD and/or annexin V labeling. At the molecular level, Cd exposure induced a decrease in hippocampal brain-derived neurotrophic factor-tropomyosin receptor kinase B (BDNF-TrkB) and Erk1/2 signaling, a significant downregulation of the expression of learning- and memory-related receptors and synaptic proteins such as the NMDAR NR2A subunit and PSD-95, as well as the expression of the synapse-specific vesicular Zn transporter ZnT3 in cultured hippocampal neurons. Zn supplementation, especially at the 30 μM concentration, led to partial or total protection against Cd neurotoxicity both with respect to the number of apoptotic cells and the expression of several genes. Interestingly, after knockdown of ZnT3 by small interfering RNA transfection, we did not find the restoration of the expression of this gene following Zn supplementation at 30 μM concentration. These data indicate the involvement of ZnT3 in the mechanism of Cd-induced hippocampal neurotoxicity.
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18.
Tissue-type plasminogen activator regulates p35-mediated Cdk5 activation in the postsynaptic terminal.
Diaz A, Jeanneret V, Merino P, McCann P, Yepes M.
J Cell Sci. 2019 Feb 28;132(5). pii: jcs224196. doi: 10.1242/jcs.224196.
Neuronal depolarization induces the synaptic release of tissue-type plasminogen activator (tPA). Cyclin-dependent kinase-5 (Cdk5) is a member of the family of cyclin-dependent kinases that regulates cell migration and synaptic function in postmitotic neurons. Cdk5 is activated by its binding to p35 (also known as Cdk5r1), a membrane-anchored protein that is rapidly degraded by the proteasome. Here, we show that tPA prevents the degradation of p35 in the synapse by a plasminogen-dependent mechanism that requires open synaptic N-methyl-D-aspartate (NMDA) receptors. We show that tPA treatment increases the abundance of p35 and its binding to Cdk5 in the postsynaptic density (PSD). Furthermore, our data indicate that tPA-induced p35-mediated Cdk5 activation does not induce cell death, but instead prevents NMDA-induced ubiquitylation of postsynaptic density protein-95 (PSD-95; also known as Dlg4) and the removal of GluR1 (also known as Gria1)-containing α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors from the PSD. These results show that the interaction between tPA and synaptic NMDA receptors regulates the expression of AMPA receptor subunits in the PSD via p35-mediated Cdk5 activation. This is a novel role for tPA as a regulator of Cdk5 activation in cerebral cortical neurons.Free Article
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19.
Mouse model of anti-NMDA receptor post-herpes simplex encephalitis.
Linnoila J, Pulli B, Armangué T, Planagumà J, Narsimhan R, Schob S, Zeller MWG, Dalmau J, Chen J.
Neurol Neuroimmunol Neuroinflamm. 2018 Dec 26;6(2):e529. doi: 10.1212/NXI.0000000000000529. eCollection 2019 Mar.
PMID:
30697582
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20.
Pyk2 in the amygdala modulates chronic stress sequelae via PSD-95-related micro-structural changes.
Montalban E, Al-Massadi O, Sancho-Balsells A, Brito V, de Pins B, Alberch J, Ginés S, Girault JA, Giralt A.
Transl Psychiatry. 2019 Jan 15;9(1):3. doi: 10.1038/s41398-018-0352-y.
PMID:
30664624
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