Hydrogen sulfide (H2S) has been widely accepted as a gas neuromodulator to regulate synaptic function. Herein, we set out to determine the effect of H2S on α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) and its mechanism.Methods:
BS3 protein cross-linking, Western blot, patch clamp, and biotin-switch assay.Results:
Bath application of H2S 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 Na2S4, 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. H2S increased S-sulfhydration of protein phosphatase type 2A (PP2A), which may be partially involved in the activation of signal pathways.Conclusion:
Our data suggest that H2S promotes surface insertion of AMPARs via phosphorylation of GluR1, which depends on a sulfhydration-mediated mechanism.