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Palmitoylation Controls NMDA Receptor Function and Steroid Sensitivity.

Pavla Hubalkova1,2, Marek Ladislav1, Vojtech Vyklicky1

  • 1Institute of Physiology CAS, Prague 4, 142 20, Czech Republic.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|February 2, 2021
PubMed
Summary

A rise in intracellular calcium enhances NMDAR sensitivity to inhibitory neurosteroids. This process, dependent on GluN2B subunit depalmitoylation, regulates NMDAR activity and offers neuroprotection.

Keywords:
NMDARcarboxy-terminal domainmolecular dynamics simulationneurosteroidpalmitoylationsingle-channel recording

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • NMDA receptors (NMDARs) are crucial for synaptic plasticity but can cause excitotoxicity when overactivated.
  • Intracellular calcium transients modulate NMDAR activity, potentially through negative feedback mechanisms.
  • Neurosteroids act as endogenous modulators of NMDAR function.

Purpose of the Study:

  • To investigate how intracellular calcium transients affect NMDAR sensitivity to neurosteroids.
  • To elucidate the molecular mechanisms underlying calcium-mediated regulation of NMDAR-steroid interactions.
  • To explore the potential neuroprotective role of this regulatory pathway.

Main Methods:

  • Electrophysiological recordings in cultured hippocampal neurons and recombinant receptors.
  • Pharmacological characterization using neurosteroids and their analogs.
  • Site-directed mutagenesis to identify key cysteine residues in the GluN2B subunit.
  • Single-channel analysis and in silico modeling.

Main Results:

  • A transient intracellular calcium rise significantly increased NMDAR sensitivity to the neurosteroid PAhPim.
  • This enhanced sensitivity was dependent on specific cysteine residues (C849, C854, C871) in the GluN2B subunit.
  • Calcium challenge induced NMDAR depalmitoylation, reducing channel opening probability.
  • In silico modeling suggested palmitoylation anchors the GluN2B C-terminus and facilitates channel opening.

Conclusions:

  • Intracellular calcium transients regulate NMDAR activity by modulating steroid sensitivity via GluN2B depalmitoylation.
  • This palmitoylation-dependent mechanism acts as an acute feedback system controlling NMDAR function.
  • Understanding this pathway may aid in developing therapeutics for neurological disorders linked to NMDAR overactivation.