4.7 Article

Palmitoylation Controls NMDA Receptor Function and Steroid Sensitivity

Journal

JOURNAL OF NEUROSCIENCE
Volume 41, Issue 10, Pages 2119-2134

Publisher

SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2654-20.2021

Keywords

carboxy-terminal domain; molecular dynamics simulation; neurosteroid; NMDAR; palmitoylation; single-channel recording

Categories

Funding

  1. Czech Science Foundation [20-17945S, 16-03913Y]
  2. Technology Agency of the Czech Republic [TN01000013]
  3. Grant Agency of Charles University [928216]
  4. ERDF/ESF project PharmaBrain [CZ.02.1.01/0.0/0.0/16_025/0007444]
  5. Research Project of the AS CR [RVO 67985823, RVO 61388963]
  6. Biotechnology and Biomedicine Center of Academy of Sciences
  7. Charles University in Vestec (European Regional Development Fund)

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Changes in NMDAR sensitivity to steroids due to alterations in intracellular Ca2+ levels serve as an acute endogenous mechanism that controls NMDAR activity.
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.

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