Palmitoylation Controls NMDA Receptor Function and Steroid Sensitivity
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F21%3A00541892" target="_blank" >RIV/67985823:_____/21:00541892 - isvavai.cz</a>
Alternative codes found
RIV/61388963:_____/21:00541892 RIV/00216208:11120/21:43921106
Result on the web
<a href="https://doi.org/10.1523/JNEUROSCI.2654-20.2021" target="_blank" >https://doi.org/10.1523/JNEUROSCI.2654-20.2021</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1523/JNEUROSCI.2654-20.2021" target="_blank" >10.1523/JNEUROSCI.2654-20.2021</a>
Alternative languages
Result language
angličtina
Original language name
Palmitoylation Controls NMDA Receptor Function and Steroid Sensitivity
Original language description
NMDARs are ligand-gated ion channels that cause an influx of Na+ and Ca2+ into postsynaptic neurons. The resulting intracellular Ca2+ transient triggers synaptic plasticity. When prolonged, it may induce excitotoxicity, but it may also activate negative feedback to control the activity of NMDARs. Here, we report that a transient rise in intracellular Ca2+ (Ca2+ challenge) increases the sensitivity of NMDARs but not AMPARs/kainate receptors to the endogenous inhibitory neurosteroid 20-oxo 5 beta-pregnan-3 alpha-yl 3-sulfate and to its synthetic analogs, such as 20-oxo-5 beta-pregnan-3 alpha-yl 3-hemipimelate (PAhPim). In cultured hippocampal neurons, 30 mu M PAhPim had virtually no effect on NMDAR responses, however, following the Ca2+ challenge, it inhibited the responses by 62%, similarly, the Ca2+ challenge induced a 3.7-fold decrease in the steroid IC50 on recombinant GluN1/GluN2B receptors. The increase in the NMDAR sensitivity to PAhPim was dependent on three cysteines (C849, C854, and C871) located in the carboxy-terminal domain of the GluN2B subunit, previously identified to be palmitoylated (Hayashi et al., 2009). Our experiments suggested that the Ca2+ challenge induced receptor depalmitoylation, and single-channel analysis revealed that this was accompanied by a 55% reduction in the probability of channel opening. Results of in silico modeling indicate that receptor palmitoylation promotes anchoring of the GluN2B subunit carboxy-terminal domain to the plasma membrane and facilitates channel opening. Depalmitoylation-induced changes in the NMDAR pharmacology explain the neuroprotective effect of PAhPim on NMDA-induced excitotoxicity. We propose that palmitoylation-dependent changes in the NMDAR sensitivity to steroids serve as an acute endogenous mechanism that controls NMDAR activity.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30103 - Neurosciences (including psychophysiology)
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2021
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Journal of Neuroscience
ISSN
0270-6474
e-ISSN
1529-2401
Volume of the periodical
41
Issue of the periodical within the volume
10
Country of publishing house
US - UNITED STATES
Number of pages
16
Pages from-to
2119-2134
UT code for WoS article
000631934700005
EID of the result in the Scopus database
2-s2.0-85102907083