Katson vanhoja ja uusia tietoja D-seriinin aineenvaihdunnasta. Seriini ei ole essentielli aminohappo, muta sen endogeeninen synteesi on monen mutkan takana.
3.
Ota Y, Zanetti AT, Hallock RM.
Neural Plast. 2013;2013:185463. doi: 10.1155/2013/185463. Epub 2013 Dec 4. Review.
- PMID:
- 24369508
EFRIINISIGNALOINTI ja GLUTAMAATINKULJETTAJAT
Efriinisignalointi (jossa ligandit ovat efriinejä tyyppiä A ja B ja reseptorit efriinireseptoreita EPH A ja APH B tyyppiä) tunnetaan osallistumisesta neuraaliseen kehitykseen, jossa se aktiinia uudelleen järjestelemällä toimii inhiboiden aksonien ja dendriittien kasvua.
Astrosyytin efriini-A3 ja neuronin dendriittiulokkeen reseptori EPHA4 tekevät keskenään interaktion vähentämällä entsyymin GLAST ja GLT-1 pitoisuuksia, jotta tapahtuisi asianmukaista synaptoitumista.
GLAST entsyymi on astrosyytin kalvossa oleva glutamaatti-aspartaatti-transporter .
GLT-1 entsyymi on postsynaptisessa kalvossa oleva glutamaatin kuljwttaja.
Astrosyytit ilmentävät sekä EPHB-reseptoreja että B-tyyppisiä efriini-ligandeja , josita aktiiisn on efriini-B3 LTP:n aikana Efriini-B3 lisää D-seriinin vapautumista säätelemällä seriinirasemaasia (SR), entsyymiä, joka muuttaa L-seriiniä -D-seriiniksi. Efriini-B3 säätelee myös SR.n kanssa interaktion tekevää proteiinikinaasia PKCalfa.
Efriini-B3 säätää spesifisesti alas PKCalfa-kinaasin, mikä aiheuttaa taas interaktiota seriinirasemaasin ja PICK1- kinaasin kesken ja siitä seuraa D-seriinin vapautumista. ( PICK1 on proteiini, joka tekee interaktion C-kinaasin kanssa).
Efriini-B3 kykenee lisäksi sitoutumaan sekä EPHB3- että EPHA4 - reseptoreihin . kun on tutkittu näiden kahden efriiniresptorin suhteen poistogeenisiä viljeltyjä astrosyyttejä ja mittailtu D-seriinipitoisuuksia, on havaittu, että molemmat reseptorit ovat välttämättömiä, jotta D-seriiniä vapautuu. Täten Efriini-A- signaloinnin säädellessä GLT-1 pitoisuuksia, efriini-B-signalointi säätelee NMDA-reseptorien aktivoismisessa tarvittavaa D-seriinipitoisuutta.
Ephrin Signaling and Glutamate Transporters
- Ephrin signaling, consisting of ephrin-As and ephrin-Bs, is known for its involvement in neural development by inhibiting axonal and dendritic growth via actin rearrangement [108–114].
- The interaction between ephrin-A3 and EphA4, which are expressed by astrocytes and dendritic spines of neurons, respectively, is involved in decreasing levels of GLAST and glutamate transporter 1 (GLT-1) for proper synapsing to occur [115–118].
- Astrocytes express both EphB receptors and ephrin-B ligands, ephrinB3 being the most active during LTP [119]. EphrinB3 enhances D-serine release by regulating serine racemase (SR), an enzyme responsible for the conversion of L-serine to D-serine, and an SR-interacting protein, protein kinase C (PKCα).
- Specifically, ephrinB3 downregulates PKCα in order to increase the interaction between SR and Protein Interacting with C-kinase (PICK1), causing D-serine release [119].
- Moreover, ephrinB3 is able to bind to both EphB3 and EphA4 receptors [120]. By measuring D-serine levels in EphB3 and EphA4 knockouts in cultured astrocytes, both receptors were necessary for D-serine release [119]. Thus, while ephrin-A signaling regulates levels of GLT-1, ephrin-B signaling regulates levels of D-serine release for activation of NMDA receptors.
HUOM. tässä on D-seriinin suojaava funktio mainittuna. Aiemmin puhuttiin vain glysiinistä tässä NMDA- reseptorin ko-agonistin kohdassa , mutta varsinainen endogeenin molekyyli on D-Seriini, joka tehostaa NMDAr signalointia hienosäädönomaisesti ja protektiivisesti.
Tieto D-seriinistä tässä funktiossa ei ole kovin vanha . Artikkeli vuodelta 2000. https://www.pnas.org/content/pnas/97/9/4926.full.pdf
D-seriinin muodostuminen ei ole kovin suoraviivaista ja saattaa komrpmittoida neuronaalista funktiota ( kognitiota ja muistitoimintaa), jos sen muodostumienn ei ole normaalia.
Haku: 9 artikkelia
Search results
Items: 9
1.
Vastagh C, Liposits Z.
Front Cell Neurosci. 2017 Jul 4;11:183. doi: 10.3389/fncel.2017.00183. eCollection 2017.
2. ( Tämä viite Luusto-blogiin luubiologiasta 12.3. 2019)
Nielson
CM, Liu CT, et al.
J Bone Miner Res. 2016 Dec;31(12):2085-2097. doi: 10.1002/jbmr.2913. Epub 2016 Sep 6.
- PMID:
- 27476799
4.
Yu X, Wang G, Gilmore A, Yee AX, Li X, Xu T, Smith SJ, Chen L, Zuo Y.
Neuron. 2013 Oct 2;80(1):64-71. doi: 10.1016/j.neuron.2013.07.014. Epub 2013 Oct 2.Refinement of mammalian neural circuits involves substantial
experience-dependent synapse elimination. Using in vivo two-photon
imaging, we found that experience-dependent elimination of postsynaptic
dendritic spines in the cortex was accelerated in ephrin-A2 knockout (KO) mice, resulting in fewer adolescent spines integrated into adult circuits. Such increased spine removal in ephrin-A2 KOs depended on activation of glutamate
receptors, as blockade of the N-methyl-D-aspartate (NMDA) receptors
eliminated the difference in spine loss between wild-type and KO mice.
We also showed that ephrin-A2 in the cortex colocalized with glial glutamate transporters, which were significantly downregulated in ephrin-A2 KOs. Consistently, glial glutamate transport was reduced in ephrin-A2 KOs, resulting in an accumulation of synaptic glutamate. Finally, inhibition of glial glutamate uptake promoted spine elimination in wild-type mice, resembling the phenotype of ephrin-A2 KOs. Together, our results suggest that ephrin-A2 regulates experience-dependent, NMDA receptor-mediated synaptic pruning through glial glutamate transport during maturation of the mouse cortex.
- PMID:
- 24094103
5.
Ong WY, Tanaka K, Dawe GS, Ittner LM, Farooqui AA.
J Alzheimers Dis. 2013;35(4):643-68. doi: 10.3233/JAD-121990. Review.Abstract
Progress is being
made in identifying possible pathogenic factors and novel genes in the
development of Alzheimer's disease (AD). Many of these could contribute
to 'slow excitotoxicity', defined as neuronal loss due to overexcitation
as a consequence of decreased energy production due, for instance, to
changes in insulin receptor signaling; or receptor abnormalities, such
as tau-induced alterations the N-methyl-D-aspartate (NMDA) receptor
phosphorylation. As a result, glutamate becomes neurotoxic at concentrations that normally show no toxicity. In AD, NMDA receptors are overexcited by glutamate
in a tonic, rather than a phasic manner. Moreover, in prodromal AD
subjects, functional MRI reveals an increase in neural network
activities relative to baseline, rather than loss of activity. This may
be an attempt to compensate for reduced number of neurons, or reflect
ongoing slow excitotoxicity. This article reviews possible links between
AD pathogenic factors such as AβPP/Aβ and tau; novel risk genes
including clusterin, phosphatidylinositol-binding clathrin assembly
protein, complement receptor 1, bridging integrator 1, ATP-binding
cassette transporter 7, membrane-spanning 4-domains subfamily A, CD2-associated protein, sialic acid-binding immunoglobulin-like lectin, and ephrin
receptor A1; metabolic changes including insulin resistance and
hypercholesterolemia; lipid changes including alterations in brain
phospholipids, cholesterol and ceramides; glial changes affecting
microglia and astrocytes; alterations in brain iron metallome and
oxidative stress; and slow excitotoxicity. Better understanding of the
possible molecular links between pathogenic factors and slow
excitotoxicity could inform our understanding of the disease, and pave
the way towards new therapeutic strategies for AD.
- PMID:
- 23481689
- DOI:
- 10.3233/JAD-121990
- PMID:
- 23481689
6.
Bouvier
D, Tremblay ME, Riad M, Corera AT, Gingras D, Horn KE, Fotouhi M,
Girard M, Murai KK, Kennedy TE, McPherson PS, Pasquale EB, Fon EA,
Doucet G.
J Neurochem. 2010 Apr;113(1):153-65. doi: 10.1111/j.1471-4159.2010.06582.x. Epub 2010 Jan 12. Abstract
EphA4, a receptor
tyrosine kinase, is expressed in various pre-, post- and peri-synaptic
organelles and implicated in the regulation of morphological and
physiological properties of synapses. It regulates synaptic plasticity
by acting as a binding partner for glial ephrin-A3 and possibly other pre- or post-synaptic ephrins. Now, its trafficking mechanisms remain unknown. In this study, we examine the association of EphA4 with transport,
clathrin-coated and synaptic vesicles using cell fractionation, vesicle
immunoisolation and electron microscopy. EphA4 was found in highly
purified fractions of clathrin-coated or synaptic vesicles. It was also
detected in vesicles immuno-isolated with antibodies anti-synaptophysin,
anti-vesicular glutamate transporter or anti-vesicular GABA transporter; demonstrating its presence in synaptic vesicles. However, it was not detected in immuno-isolated piccolo-bassoon transport vesicles. In vivo and in dissociated cultures, EphA4 was localized by immunoelectron microscopy in vesicular glutamate transporter
1-(GLUT-1)positive terminals of hippocampal neurons. Remarkably, the cell
surface immunofluorescence of EphA4 increased markedly in cultured
hippocampal neurons following KCl depolarization. These observations
indicate that EphA4 is present in subsets of synapcltic vesies, can be
externalized during depolarization, and internalized within
clathrin-coated vesicles. This trafficking itinerary may serve to
regulate the levels of EphA4 in the synaptic plasma membrane and thereby
modulate signaling events that contribute to synaptic plasticity.
- PMID:
- 20067584
7.
Filosa
A, Paixão S, Honsek SD, Carmona MA, Becker L, Feddersen B, Gaitanos L,
Rudhard Y, Schoepfer R, Klopstock T, Kullander K, Rose CR, Pasquale EB,
Klein R.
Nat Neurosci. 2009 Oct;12(10):1285-92. doi: 10.1038/nn.2394. Epub 2009 Sep 6. Abstract
Astrocytes
are critical participants in synapse development and function, but
their role in synaptic plasticity is unclear. Eph receptors and their ephrin ligands have been suggested to regulate neuron-glia interactions, and EphA4-mediated ephrin
reverse signaling is required for synaptic plasticity in the
hippocampus. Here we show that long-term potentiation (LTP) at the
CA3-CA1 synapse is modulated by EphA4 in the postsynaptic CA1 cell and
by ephrin-A3, a ligand of EphA4 that is found in astrocytes. Lack of EphA4 increased the abundance of glial glutamate transporters (GLAST), and ephrin-A3 modulated transporter currents in astrocytes. Pharmacological inhibition of glial glutamate transporters rescued the LTP defects in EphA4 (Epha4) and ephrin-A3 (Efna3) mutant mice. Transgenic overexpression of ephrin-A3 in astrocytes reduces glutamate transporter levels and produces focal dendritic swellings possibly caused by glutamate excitotoxicity. These results suggest that EphA4/ephrin-A3 signaling is a critical mechanism for astrocytes to regulate synaptic function and plasticity.
- PMID:
- 19734893
8.
Carmona MA, Murai KK, Wang L, Roberts AJ, Pasquale EB.
Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12524-9. doi: 10.1073/pnas.0903328106. Epub 2009 Jul 10.Increasing evidence indicates the importance of neuron-glia
communication for synaptic function, but the mechanisms involved are not
fully understood. We reported that the EphA4 receptor tyrosine kinase
is in dendritic spines of pyramidal neurons of the adult hippocampus and
regulates spine morphology. We now show that the ephrin-A3
ligand, which is located in the perisynaptic processes of astrocytes,
is essential for maintaining EphA4 activation and normal spine
morphology in vivo. Ephrin-A3-knockout mice have spine irregularities similar to those observed in EphA4-knockout mice. Remarkably, loss of ephrin-A3 or EphA4 increases the expression of glial glutamate transporters. Consistent with this, glutamate transport is elevated in ephrin-A3-null hippocampal slices whereas Eph-dependent stimulation of ephrin-A3 signaling inhibits glutamate transport. Furthermore, some forms of hippocampus-dependent learning are impaired in the ephrin-A3-knockout mice. Our results suggest that the interaction between neuronal EphA4 and glial ephrin-A3 bidirectionally controls synapse morphology and glial glutamate transport, ultimately regulating hippocampal function.
- PMID:
- 19592509
9.
Ogawa Y, Takebayashi H, Takahashi M, Osumi N, Iwasaki Y, Ikenaka K.
Dev Neurosci. 2005;27(6):364-77.
- PMID:
- 16280634
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