Palmitoylation Controls NMDA Receptor Function and Steroid Sensitivity

0541892 - FGÚ 2022 RIV US eng J - Článek v odborném periodiku
Hubálková, Pavla - Ladislav, Marek - Vyklický, Vojtěch - Smejkalová, Tereza - Hrčka Krausová, Barbora - Kysilov, Bohdan - Krůšek, Jan - Naimová, Žaneta - Kořínek, Miloslav - Chodounská, Hana - Kudová, Eva - Černý, Jiří - Vyklický ml., Ladislav
Palmitoylation Controls NMDA Receptor Function and Steroid Sensitivity.
Journal of Neuroscience. Roč. 41, č. 10 (2021), s. 2119-2134. ISSN 0270-6474. E-ISSN 1529-2401
Grant CEP: GA ČR(CZ) GA20-17945S; GA ČR(CZ) GJ16-03913Y; GA TA ČR(CZ) TN01000013; GA MŠMT(CZ) LQ1604; GA MZd(CZ) EF16_025/0007444
Institucionální podpora: RVO:67985823 ; RVO:61388963
Klíčová slova: carboxy-terminal domain * molecular dynamics simulation * neurosteroid * NMDAR * palmitoylation * single-channel recording
Obor OECD: Neurosciences (including psychophysiology
Impakt faktor: 6.709, rok: 2021
Způsob publikování: Open access s časovým embargem
https://doi.org/10.1523/JNEUROSCI.2654-20.2021

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.
Trvalý link: http://hdl.handle.net/11104/0319387