Hydrogen Sulfide Promotes Surface Insertion of Hippocampal AMPA Receptor GluR1 Subunit via Phosphorylating at Serine-831/Serine-845 Sites Through a Sulfhydration-Dependent Mechanism.

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Hydrogen sulfide (H2 S) has been widely accepted as a gas neuromodulator to regulate synaptic function. Herein, we set out to determine the effect of H2 S on α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) and its mechanism. BS(3) protein cross-linking, Western blot, patch clamp, and biotin-switch assay. Bath application of H2 S donor NaHS (50 and 100 μM) rapidly promoted surface insertion of hippocampal AMPAR GluR1 subunit. This effect can be abolished by dithiothreitol (DTT) and mimicked by Na2 S4 , indicating that a sulfhydration-dependent mechanism may be involved. NaHS increased APMAR-mediated EPSC and led to an elevation of GluR2-lacking AMPAR content. Notably, NaHS did not increase the sulfhydration of AMPAR subunits, but it significantly increased the phosphorylation of GluR1 at serine-831 and serine-845 sites. Postsynaptic signal pathways that control GluR1 phosphorylation, such as protein kinase A (PKA), protein kinase C, and calcium/calmodulin-dependent protein kinases II (CaMKII), were sulfhydrated, activated by NaHS, and these effects can be occluded by DTT. H2 S increased S-sulfhydration of protein phosphatase type 2A (PP2A), which may be partially involved in the activation of signal pathways. Our data suggest that H2 S promotes surface insertion of AMPARs via phosphorylation of GluR1, which depends on a sulfhydration-mediated mechanism.