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Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
Published on: August 16, 2018
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Forskolin reverses the O-GlcNAcylation dependent decrease in GABAAR current amplitude at hippocampal synapses
Biorxiv : the Preprint Server for Biology
|March 18, 2024
Summary
Increased O-GlcNAcylation unmasks neurosteroid potentiation of GABAergic transmission, reversing prior depression. This reveals a novel interaction between O-GlcNAcylation and neurosteroids in synaptic inhibition.
Area of Science:
- Neuroscience
- Cellular Biology
- Biochemistry
Background:
- Post-translational modifications like phosphorylation and O-GlcNAcylation regulate GABAergic transmission.
- O-GlcNAcylation, the addition of N-acetylglucosamine to serine/threonine residues, was previously shown to depress inhibitory postsynaptic currents (IPSCs).
- The interaction between O-GlcNAcylation and phosphorylation in modulating GABAergic signaling remains unclear.
Approach:
- Hippocampal principal cells were used to record inhibitory postsynaptic currents (IPSCs).
- O-GlcNAcylation was pharmacologically increased, followed by or preceded by increased serine phosphorylation using forskolin.
- The effects of neurosteroids THDOC and progesterone on eIPSCs were assessed under heightened O-GlcNAcylation.
Key Points:
- Prior O-GlcNAcylation enhancement unmasked a forskolin-dependent potentiation of eIPSC amplitude, reversing O-GlcNAc-induced depression.
- This potentiation was independent of adenylate cyclase or protein kinase A, suggesting serine phosphorylation is not the direct mechanism.
- Increased O-GlcNAcylation also unmasked potentiating effects of neurosteroids THDOC and progesterone on eIPSC amplitude.
Conclusions:
- Heightened O-GlcNAcylation facilitates neurosteroid potentiation of synaptic GABA receptors (GABAARs).
- This interaction allows neurosteroid agonists to access their sites on synaptic GABAARs, strengthening synaptic inhibition.
- O-GlcNAcylation plays a critical role in regulating the sensitivity of GABAergic synapses to neurosteroids.
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