Amyloidibeeta interaktomi analyysi ( 2011). useita Znf proteiineja joukossa.

https://pubs.acs.org/doi/abs/10.1021/pr1009096

 Protein Array Based Interactome Analysis of Amyloid-β Indicates an Inhibition of Protein Translation

Dezso P. Virok^*†
Dóra Simon^‡

View Author Information

Cite this: J. Proteome Res. 2011, 10, 4, 1538-1547

Publication Date:January 19, 2011

https://doi.org/10.1021/pr1009096

Oligomeric amyloid-β is currently of interest in amyloid-β mediated toxicity and the pathogenesis of Alzheimer’s disease. Mapping the amyloid-β interaction partners could help to discover novel pathways in disease pathogenesis. To discover the amyloid-β interaction partners, we applied a protein array with more than 8100 unique recombinantly expressed human proteins. We identified 324 proteins as potential interactors of oligomeric amyloid-β. The Gene Ontology functional analysis of these proteins showed that oligomeric amyloid-β bound to multiple proteins with diverse functions both from extra and intracellular localizations. This undiscriminating binding phenotype indicates that multiple protein interactions mediate the toxicity of the oligomeric amyloid-β. The most highly impacted cellular system was the protein translation machinery. Oligomeric amyloid-β could bind to altogether 24 proteins involved in translation initiation and elongation. The binding of amyloid-β to purified rat hippocampal ribosomes validated the protein array results. More importantly, in vitro translation assays showed that the oligomeric amyloid-β had a concentration dependent inhibitory activity on translation. Our results indicate that the inhibited protein synthesis is one of the pathways that can be involved in the amyloid-beta induced neurotoxicity.

KEYWORDS (keywords):
Alzheimer’s
oligomeric
amyloid-β
protein array
protein chip
proteomics
interactome

      normalized signal intensity 
Protein Header Gene Symbol Database ID Ultimate ORF ID Swissprot ID  Array A Array B
  P2293    7110,22 7245,60
  PV4690    6835,22 8718,84
WD repeat domain 5 (WDR5), transcript variant 1 WDR5 NM_017588.1 IOH4895 P61964  6279,74 8539,23
signal recognition particle 19kDa (SRP19) SRP19 BC010947.1 IOH14455 P09132  6076,43 3232,90
hypothetical protein MGC42630 (MGC42630) FAM27E3 NM_175923.2 IOH22051 Q08E93  4909,23 4141,35
SUMO1/sentrin/SMT3 specific peptidase 2 (SENP2) SENP2 NM_021627.2 IOH26311 Q9HC62  3572,22 4621,71
DEAD (Asp-Glu-Ala-Asp) box polypeptide 18 (DDX18) DDX18 BC003360.1 IOH2892 Q9NVP1  3569,76 5607,45
RNA binding motif protein 11 (RBM11) RBM11 NM_144770.1 IOH22581 P57052  3386,34 2756,28
chromosome 12 open reading frame 52 (C12orf52) C12orf52 NM_032848.1 IOH13466 Q96K30  3103,24 5477,67
variable charge, Y-linked 1B (VCY) VCY BC056508.1 IOH29456 O14598  2827,13 3931,10
SECIS binding protein 2 (SECISBP2) SECISBP2 BC036109.1 IOH27253 Q96T21  2813,28 9535,04
hexokinase 1 (HK1) HK1 BC008730.2 IOH5942 P19367  2756,41 2624,89
Pumilio domain-containing protein KIAA0020 KIAA0020 NM_014878.2 IOH10030 Q15397  2648,09 3024,14
LTV1 homolog (S. cerevisiae) (LTV1) LTV1 NM_032860.2 IOH22948 Q96GA3  2627,18 1946,10
PP2C-like domain-containing protein C3orf48 C3orf48 NM_144714.1 IOH11221 A8MPX8  2626,93 4930,28
zinc finger protein 22 (KOX 15) (ZNF22) ZNF22 BC010642.1 IOH9701 P17026  2618,53 4538,58
olfactory receptor, family 6, subfamily B, member 3 (OR6B3), mRNA OR6B3 AB065662.1 IOH28287 Q8NGW1  2549,07 999,95
chromosome 3 open reading frame 37 (C3orf37) C3orf37 BC009993.2 IOH27830 Q96FZ2  2491,57 2484,15
guanine nucleotide binding protein-like 2 (nucleolar) (GNL2) GNL2 BC009250.1 IOH27775 Q13823  2316,56 4556,13
tubulin, gamma 1 (TUBG1) TUBG1 NM_001070.1 IOH4241 P23258  2312,38 3332,08
PDZ domain-containing protein 4 PDZD4 BC002606.1 IOH4132 Q76G19  2228,66 2043,16
arginine vasopressin-induced 1 (AVPI1) AVPI1 BC000877.1 IOH3268 Q5T686  2211,16 1588,71
general transcription factor IIE, polypeptide 2, beta 34kDa (GTF2E2) GTF2E2 NM_002095.1 IOH22963 P29084  2205,65 2998,21
occludin/ELL domain containing 1 (OCEL1) OCEL1 NM_024578.1 IOH23128 Q9H607  2186,50 2493,36
fibroblast growth factor 12 (FGF12), transcript variant 1 FGF12 NM_021032.2 IOH35339 P61328  2184,15 1519,12
ets variant gene 3 (ETV3) ETV3 NM_005240.1 IOH13301 P41162  2123,09 4535,51
PIN2-interacting protein 1 (PINX1) PINX1 BC015479.1 IOH11268 Q96BK5  2117,48 1544,14
nucleolar and coiled-body phosphoprotein 1 (NOLC1) NOLC1 BC006769.1 IOH3146 Q14978  2107,19 6902,87
small nuclear ribonucleoprotein 70kDa polypeptide (RNP antigen) (SNRP70) SNRP70 NM_003089.4 IOH40192 P08621  2104,52 6018,96
TATA box binding protein (TBP)-associated factor, RNA polymerase I, B, 63kDa (TAF1B) TAF1B BC018137.1 IOH10369 Q53T94  2100,47 2874,62
ribosomal protein L31 (RPL31), transcript variant 1 RPL31 NM_000993.2 IOH14051 P62899  2099,69 2492,06
ribosomal protein S16 (RPS16) RPS16 NM_001020.2 IOH13828 P62249  2054,42 3402,04
Phytanoyl-CoA dioxygenase domain-containing protein 1 PHYHD1 NM_174933.2 IOH12686 Q5SRE7  2007,02 1534,02
fibroblast growth factor 12 (FGF12), transcript variant 2 FGF12 NM_004113.3 IOH34727 P61328  1998,76 2687,61
activator of basal transcription 1 (ABT1) ABT1 NM_013375.2 IOH1920 Q9ULW3  1961,12 1638,59
eukaryotic translation initiation factor 2C, 1 (EIF2C1) EIF2C1 BC063275.1 IOH40423 Q9UL18  1951,40 2309,47
mitochondrial ribosomal protein S18A (MRPS18A), nuclear gene encoding mitochondrial protein MRPS18A NM_018135.2 IOH12060 Q9NVS2  1921,66 2847,10
DEAD (Asp-Glu-Ala-Asp) box polypeptide 10 (DDX10) DDX10 NM_004398.2 IOH38427 Q13206  1900,80 2427,42
zinc finger protein 684 (ZNF684) ZNF684 NM_152373.2 IOH14361 Q5T5D7  1893,68 3233,24
intestinal cell (MAK-like) kinase (ICK), transcript variant 1 ICK NM_014920.2 IOH38087 Q9UPZ9  1888,31 1321,44
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) GAPDH NM_002046.2 IOH3380 P04406  1857,17 1394,76
bobby sox homolog (Drosophila) (BBX) BBX NM_020235.2 IOH44025 Q8WY36  1843,23 5121,71
chromosome 18 open reading frame 56 (C18orf56) C18orf56 BC028301.1 IOH11759 Q8TAI1  1837,02 1453,78
zinc finger protein 747 (ZNF747) ZNF747 NM_023931.1 IOH3950 Q9BV97  1832,78 3096,57
fibroblast growth factor 13 (FGF13), transcript variant 1A FGF13 NM_004114.2 IOH13832 Q92913  1818,27 1295,24
MYB binding protein (P160) 1a (MYBBP1A) MYBBP1A BC050546.1 IOH26928 Q9BQG0  1796,01 2583,47
UTP14, U3 small nucleolar ribonucleoprotein, homolog A (yeast) (UTP14A) UTP14A BC001149.1 IOH4457 Q9BVJ6  1768,08 3006,02
calcium/calmodulin-dependent protein kinase kinase 2, beta (CAMKK2) CAMKK2 BC026060.2 IOH12294 Q96RR4  1751,72 2227,90
v-myc myelocytomatosis viral oncogene homolog (avian) (MYC) MYC BC000141.1 IOH2954 P01106  1706,09 740,84
dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 2 (DYRK2), transcript variant 1 DYRK2 NM_003583.2 IOH2412 Q92630  1683,98 1931,17
RNA binding motif protein 34 (RBM34) RBM34 NM_015014.1 IOH23193 P42696  1682,76 1236,80
zinc finger CCCH-type containing 3 (ZC3H3) ZC3H3 BC034435.1 IOH21500 Q8IXZ2  1660,73 3548,28
inhibitor of growth family, member 2 (ING2) ING2 NM_001564.1 IOH22913 Q9H160  1635,98 2687,19
ubiquitin specific peptidase 2 (USP2) USP2 BC002955.1 IOH4931 O75604  1625,07 1150,06
zinc finger protein 622 (ZNF622) ZNF622 NM_033414.1 IOH10240 Q969S3  1581,93 1041,84
TGF-beta receptor type-2 TGFBR2 BC040499.1 IOH27240 P37173  1577,35 1738,98
Fanconi anemia, complementation group M (FANCM) FANCM BC036056.1 IOH27184 Q8IYD8  1577,11 2227,13
THAP domain containing 4 (THAP4) THAP4 NM_015963.4 IOH40797 Q8WY91  1563,75 1797,27
PHD finger protein 8 (PHF8) PHF8 BC053861.1 IOH28930 Q9UPP1  1515,09 2104,93
chromosome 9 open reading frame 43 (C9orf43) C9orf43 NM_152786.1 IOH11171 Q8TAL5  1456,72 1888,16
cytoplasmic polyadenylation element binding protein 1 (CPEB1) CPEB1 BC035348.1 IOH28673 Q9BZB8  1455,67 2662,34
histone cluster 2, H2ac (HIST2H2AC) HIST2H2AC NM_003517.2 IOH29296 Q16777  1448,87 1904,62
Uncharacterized protein C7orf50 C7orf50 NM_032350.3 IOH6347 Q9BRJ6  1447,63 1941,87
ADAM metallopeptidase domain 22 (ADAM22) ADAM22 BC036029.1 IOH27232 Q9P0K1  1439,91 1768,58
excision repair cross-complementing rodent repair deficiency, complementation group 1 (includes overlapping antisense sequence) (ERCC1) ERCC1 BC052813.1 IOH29045 P07992  1436,51 778,43
pescadillo homolog 1, containing BRCT domain (zebrafish) (PES1) PES1 NM_014303.2 IOH21738 O00541  1427,79 1551,73
suppressor of cytokine signaling 5 (SOCS5) SOCS5 BC032862.1 IOH27139 O75159  1407,51 2254,47
dpy-19-like 2 pseudogene 4 (C. elegans) (DPY19L2P4) LOC554208 BC047471.1 IOH26529 Q86X12  1406,77 1943,02
Protein ZNF365 ZNF365 BC070073.1 IOH40070 Q70YC5  1403,99 2140,75
Wolf-Hirschhorn syndrome candidate 1 (WHSC1), transcript variant 5 WHSC1 NM_133332.1 IOH38113 O96028  1401,24 2409,90
protein tyrosine phosphatase, non-receptor type 12 (PTPN12) PTPN12 NM_002835.2 IOH28818 Q05209  1373,53 1801,50
ankyrin repeat and zinc finger domain containing 1 (ANKZF1) ANKZF1 BC000238.1 IOH4394 Q9H8Y5  1370,61 2532,16
ribosomal protein L3-like (RPL3L) RPL3L NM_005061.2 IOH26731 Q92901  1362,03 1458,56
IMP4, U3 small nucleolar ribonucleoprotein, homolog (yeast) (IMP4) IMP4 NM_033416.1 IOH12991 Q96G21  1358,14 1653,58
chromosome 8 open reading frame 33 (C8orf33) C8orf33 NM_023080.1 IOH13369 Q9H7E9  1355,97 1557,62
activation-induced cytidine deaminase (AICDA) AICDA NM_020661.1 IOH6382 Q546Y9  1355,44 1363,86
ligand of numb-protein X 1 (LNX1) LNX1 BC022983.1 IOH10747 Q8TBB1  1346,43 2079,80
death effector domain containing (DEDD), transcript variant 2 DEDD NM_004216.2 IOH14789 O75618  1335,77 1492,74
Ataxin-7-like protein 3 DKFZp761G2113 XM_375456.2 IOH43380 Q14CW9  1333,88 1061,27
Uncharacterized protein C6orf201 C6orf201 NM_206834.1 IOH40081 Q7Z4U5  1320,72 1843,81
ankyrin repeat and sterile alpha motif domain containing 6 (ANKS6) ANKS6 BC064367.1 IOH39904 Q68DC2  1313,67 704,43
PREDICTED: Homo sapiens hypothetical gene supported by NM_153241 (LOC442774) MGC42157 XM_499573.1 IOH22041 NA  1303,04 1354,58
AE binding protein 2 (AEBP2) AEBP2 NM_153207.2 IOH14301 Q96BG3  1299,74 1361,00
TRAF3-interacting protein 1 TRAF3IP1 BC059174.1 IOH28851 Q8TDR0  1298,92 1990,92
leucine rich repeat containing 8 family, member D (LRRC8D) LRRC8D BC009486.1 IOH22946 Q7L1W4  1284,92 2688,00
TBP-like 1 (TBPL1) TBPL1 BC000381.2 IOH3454 P62380  1276,34 2315,63
Kruppel-like factor 12 (KLF12) KLF12 NM_007249.3 IOH10654 Q9Y4X4  1272,22 1104,63
  BC006423.1    1269,40 2013,80
kinesin family member 3A (KIF3A) KIF3A NM_007054.1 IOH26900 Q9Y496  1249,02 1975,97
histone cluster 1, H2bm (HIST1H2BM) HIST1H2BM NM_003521.2 IOH40169 Q99879  1238,03 3276,52
Disks large-associated protein 5 DLG7 BC016276.1 IOH13621 Q15398  1226,51 2127,15
pituitary tumor-transforming 2 (PTTG2) PTTG2 NM_006607.1 IOH40244 Q9UNJ6  1226,06 2417,04
eukaryotic translation initiation factor 2C, 4 (EIF2C4) EIF2C4 NM_017629.2 IOH38411 Q9HCK5  1217,51 2117,44
casein kinase 1, epsilon (CSNK1E), transcript variant 2 CSNK1E NM_001894.2 IOH21160 P49674  1215,88 1263,57
chromosome 10 open reading frame 80 (C10orf80) C10orf80 NM_001008723.1 IOH43999 Q5T655  1213,37 1154,93
apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3H (APOBEC3H) APOBEC3H BC069023.1 IOH40776 A8MV17  1204,18 2796,81
mitochondrial ribosomal protein L34 (MRPL34), nuclear gene encoding mitochondrial protein MRPL34 NM_023937.1 IOH4594 Q9BQ48  1193,89 2393,34
DEAD (Asp-Glu-Ala-Asp) box polypeptide 49 (DDX49) DDX49 NM_019070.1 IOH5264 Q9Y6V7  1193,01 656,92
olfactory receptor, family 4, subfamily D, member 6 (OR4D6) OR4D6 NM_001004708.1 IOH28245 Q8NGJ1  1190,23 1760,91
heterochromatin protein 1, binding protein 3 (HP1BP3) HP1BP3 NM_016287.2 IOH43530 Q5SSJ5  1188,24 2291,86
UPF3 regulator of nonsense transcripts homolog A (yeast) (UPF3A) UPF3A BC023569.1 IOH27860 A2A366  1185,97 863,55
DEAD (Asp-Glu-Ala-Asp) box polypeptide 55 (DDX55) DDX55 BC030020.2 IOH22410 Q8NHQ9  1183,21 1595,26
RNA-binding protein 42 MGC10433 BC031682.1 IOH22859 Q9BTD8  1176,92 1113,02
ribos

RPH3A (12q24.13) , RABPHILIN 3A , exofiliini-1, ( 133 artikkelia)

https://www.ncbi.nlm.nih.gov/pubmed/?term=Rabphilin+3A

Haku: Geeni Rabphilin 3A  ( Huom.  luin tmän proteiinin olemassaolosta vasta eilen 16.12.2019)

Official Symbol

RPH3Aprovided by HGNC

Official Full Name

rabphilin 3Aprovided by HGNC

Summary

The protein encoded by this gene is thought to be an effector for RAB3A, which is a small G protein that acts in the late stages of neurotransmitter exocytosis. The encoded protein may be involved in neurotransmitter release and synaptic vesicle traffic. [provided by RefSeq, Dec 2016]

Expression

Biased expression in brain (RPKM 30.1) and adrenal (RPKM 1.7) See more

Orthologs

mouse all

Preferred Names

rabphilin-3A

Names

exophilin-1

rabphilin 3A homolog

Genomic context

See RPH3A in Genome Data Viewer

Location:

12q24.13

Exon count:

27
https://www.ncbi.nlm.nih.gov/protein/NP_001137326.1

Conserved Domains (3) summary

cd04035
Location:393 → 516

C2A_Rabphilin_Doc2; C2 domain first repeat present in Rabphilin and Double C2 domain ( Ca2++ binding  domain)

cd08384
Location:553 → 685

C2B_Rabphilin_Doc2; C2 domain second repeat present in Rabphilin and Double C2 domain

(C2 domain second repeat present in Rabphilin and Double C2 domain

Rabphilin is found neurons and in neuroendrocrine cells, while Doc2 is found not only in the brain but in tissues, including mast cells, chromaffin cells, and osteoblasts. Rabphilin and Doc2s share highly homologous tandem C2 domains, although their N-terminal structures are completely different: rabphilin contains an N-terminal Rab-binding domain (RBD),7 whereas Doc2 contains an N-terminal Munc13-1-interacting domain (MID). C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-I topology.

cd15762
Location:92 → 171

FYVE_RP3A; FYVE-related domain found in rabphilin-3A and similar proteins

FYVE-related domain found in rabphilin-3A and similar proteins

Rabphilin-3A, also termed exophilin-1, is an effector protein that binds to the GTP-bound form of Rab3A, which is one of the most abundant Rab proteins in neurons and predominantly localized to synaptic vesicles. Rabphilin-3A is homologous to alpha-Rab3-interacting molecules (RIMs). It is a multi-domain protein containing an N-terminal Rab3A effector domain, a proline-rich linker region, and two tandem C2 domains. The effector domain binds specifically to the activated GTP-bound state of Rab3A and harbors a conserved FYVE zinc finger. The C2 domains are responsible for the binding of phosphatidylinositol-4,5-bisphosphate (PIP2) , a key player in the neurotransmitter release process. Thus, Rabphilin-3A has also been implicated in vesicle trafficking. The FYVE domain of Rabphilin-3A resembles a FYVE-related domain that is structurally similar to the canonical FYVE domains but lacks the three signature sequences: an N-terminal WxxD motif (x for any residue), the central basic R(R/K)HHCRxCG patch, and a C-terminal RVC motif.

Feature 1: Zn binding site [ion binding site], 8 residue positions

Conserved feature residue pattern:C C C C C C C C

Evidence:

• Structure:1ZBD; Rattus norvegicus Rabphilin-3A binds two Zn2+ through its effector domain.
  - View structure with Cn3D
• Citation:PMID 10025402

ite            order(98,101,115,118,123,126,140,143)
                     /site_type="other"
                     /note="Zn binding site [ion binding]"
                     /db_xref="CDD:277301"

ORIGIN      
        1 mtdtvfsnss nrwmypsdrp lqsndkeqlq agwsvhpggq pdrqrkqeel tdeekeiinr
       61 viaraekmee meqerigrlv drlenmrknv agdgvnrCil Cgeqlgmlgs acvvCedCkk
      121 nvCtkCgvet nnrlhsvwlC kiCieqrevw krsgawffkg fpkqvlpqpm pikktkpqqp
      181 vsepaapeqp apepkhpara pargdsedrr gpgqktgpdp asapgrgnyg ppvrrasear
      241 mssssrdses wdhsggagds srspaglrra nsvqasrpap gsvqspappq pgqpgtpggs
      301 rpgpgpagrf pdqkpevaps dpgttappre ertggvggyp avgaredrms hpsgpysqas
      361 aaapqpaaar qppppeeeee eansydsdea ttlgalefsl lydqdnsslq ctiikakglk
      421 pmdsngladp yvklhllpga sksnklrtkt lrntrnpiwn etlvyhgitd edmqrktlri
      481 svcdedkfgh nefigetrfs lkklkpnqrk nfniclervi pmkragttgs argmalyeee
      541 qvervgdiee rgkilvslmy stqqgglivg iircvhlaam dangysdpfv klwlkpdmgk
      601 kakhktqikk ktlnpefnee ffydikhsdl akksldisvw dydigksndy iggcqlgisa
      661 kgerlkhwye clknkdkkie rwhqlqnenh vssd
//

Select item 314011964.

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

Similar articles


katsottava yhteys Ach erg. neurons,rabphilin3A?

Neurochem Int. 2014 Jan;64:29-36. doi: 10.1016/j.neuint.2013.10.013. Epub 2013 Nov 5.

Decreased rabphilin 3A immunoreactivity in Alzheimer's disease is associated with Aβ burden.

Tan MG¹, Lee C², Lee JH², Francis PT³, Williams RJ⁴, Ramírez MJ⁵, Chen CP⁶, Wong PT⁶, Lai MK⁷.

Abstract
Synaptic dysfunction, together with neuritic plaques, neurofibrillary tangles and cholinergic neuron loss is an established finding in the Alzheimer's disease (AD) neocortex. The synaptopathology of AD is known to involve both pre- and postsynaptic components. However, the status of rabphilin 3A (RPH3A), which interacts with the SNARE complex and regulates synaptic vesicle exocytosis and Ca(2+)-triggered neurotransmitter release, is at present unclear. In this study, we measured RPH3A and its ligand Rab3A as well as several SNARE proteins in postmortem neocortex of patients with AD, and found specific reductions of RPH3A immunoreactivity compared with aged controls. RPH3A loss correlated with dementia severity, cholinergic deafferentation, and increased β-amyloid (Aβ) concentrations. Furthermore, RPH3A expression is selectively downregulated in cultured neurons treated with Aβ25-35 peptides. Our data suggest that presynaptic SNARE dysfunction forms part of the synaptopathology of AD.

NMDA reseptorin stabiliteetti ja USP6 (DUB) deubikitinaasi

Hakusana: Ubiquitylation of PSD-95?
Vastausartikkeli: https://www.ncbi.nlm.nih.gov/pubmed/31841517

PLoS Biol. 2019 Dec 16;17(12):e3000525. doi: 10.1371/journal.pbio.3000525. eCollection 2019 Dec.

The deubiquitinase USP6 affects memory and synaptic plasticity through modulating NMDA receptor stability.

Zeng F¹, Ma X^1,2, Zhu L¹, Xu Q¹, Zeng Y¹, Gao Y¹, Li G¹, Guo T¹, Zhang H¹, Tang X³, Wang Z⁴, Ye Z^1,5, Zheng L⁶, Zhang H¹, Zheng Q¹, Li K¹, Lu J¹, Qi X¹, Luo H¹, Zhang X¹, Wang Z^1,5, Zhou Y⁶, Yao Y⁷, Ke R⁴, Zhou Y⁸, Liu Y³, Sun H¹, Huang T⁹, Shao Z¹, Xu H⁹, Wang X¹.

1

State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China.

2

School of Life Sciences, Xinjiang Normal University, Urumqi, China.

3

Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical University, Nanjing, China.

4

School of Biomedical Sciences, Huaqiao University, Quanzhou, China.

5

Department of Neurosurgery, the First Affiliated Hospital of Xiamen University, Xiamen, China.

6

Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, China.

7

Department of Functional Neurosurgery, Xiamen Humanity Hospital, Xiamen, China.

8

Department of Translational Medicine, School of Medicine, Xiamen University, Xiamen, China.

9

Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America.

Abstract

Ubiquitin-specific protease (USP) 6 is a hominoid deubiquitinating enzyme (DUB) previously implicated in intellectual disability and autism spectrum disorder. Although these findings link USP6 to higher brain function, potential roles for USP6 in cognition have not been investigated. Here, we report that USP6 is highly expressed in induced human neurons and that neuron-specific expression of USP6 enhances learning and memory in a transgenic mouse model. Similarly, USP6 expression regulates N-methyl-D-aspartate-type glutamate receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD)in USP6 transgenic mouse hippocampi. Proteomic characterization of transgenic USP6 mouse cortex reveals attenuated NMDAR ubiquitination, with concomitant elevation in NMDAR expression, stability, and cell surface distribution with USP6 overexpression. USP6 positively modulates GluN1 expression in transfected cells, and USP6 down-regulation impedes focal GluN1 distribution at postsynaptic densities and impairs synaptic function in neurons derived from human embryonic stem cells. Together, these results indicate that USP6 enhances NMDAR stability to promote synaptic function and cognition.

PMID:

31841517

DOI:

10.1371/journal.pbio.3000525

 

HAKU: PSD-95 (AND) NMDAr

See Gene information for nmdar psd95

nmdar in Mus musculus (2)Drosophila melanogaster (2)All 4 Gene records
psd95 in Homo sapiensMus musculus (2)Rattus norvegicusAll 5 Gene records

See also: 2 tests for PSD95 in the Genetic Testing Registry

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Talletan sitaatit  tämän vuoden  tieteellisistä tuloksista (2019)

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Select item 318318391.

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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Select item 317428332.

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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Select item 315189013.

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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Select item 314011964.

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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Select item 313761585.

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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Select item 312724786.

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.
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Select item 312631907.

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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Select item 312356858.

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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Select item 312344169.

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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Select item 3116693910.

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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Select item 3110291711.

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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Select item 3090965912.

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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Select item 3088133913.

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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Select item 3076647614.

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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Select item 3074703415.

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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Select item 3074051816.

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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Select item 3071413317.

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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Select item 3070991818.

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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Select item 3069758219.

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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Select item 3066462420.

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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Juomaveden fluoridi ja mikrogliavaikutus

https://www.ncbi.nlm.nih.gov/pubmed/30273629
Pohdittavaksi 

Kortikaaliset proteiiniverkot ja PDZ- domaanit. NMDA reseptori

https://www.cell.com/current-biology/fulltext/S0960-9822(96)00737-3?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0960982296007373%3Fshowall%3Dtrue

Dispatch| Volume 6, ISSUE 11, P1385-1388, November 01, 1996

Protein–protein interactions: PDZ domain networks

• Alan S. Fanning
• James Melvin Anderson

Open ArchiveDOI:https://doi.org/10.1016/S0960-9822(96)00737-3




Biochemical analyses using both in vivo and in vitro binding assays suggest that PDZ domains are modular protein-binding domains that have at least two distinct mechanisms for binding: they can bind to specific recognition sequences at the carboxyl termini of proteins, or they can dimerize with other PDZ domains. For example, the carboxyl termini of both the N-methyl D-aspartate (NMDA) receptor and the Shaker-type potassium channel have been identified as ligands for the first (PDZ 1) and second (PDZ 2) PDZ domains of three related proteins — the synapse-associated proteins PSD-95, chapsyn 110 and the human homolog of the Drosophila Dlg protein (hdlg) [

4

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5

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6

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7

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