Potentiation of Surface Stability of AMPA Receptors by Sulfhydryl Compounds: A Redox-Independent Effect by Disrupting Palmitoylation

Sulfhydryl compounds such as dithiothreitol (DTT) and β-mercaptoethanol (β-ME) are widely used as redox agents. Previous studies in our group and other laboratory have reported the effect of sulfhydryl compounds on the function of glutamate receptor, including plasticity. Most of these findings have focused on the N -methyl- d -aspartic acid receptor, in contrast, very little is known about the effect of sulfhydryl compounds on α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR). Here, we observed that DTT (100 μM), β-ME (200 μM) and l -cysteine (200 μM) significantly elevated the surface expression of AMPARs via reducing their palmitoylation in rat hippocampal slices in vitro . Increased surface stability of AMPARs was not be correlated with the altered redox status, because the chemical entities containing mercapto group such as penicillamine (200 μM) and 2-mercapto-1-methylimidazole (200 μM) exhibited little effects on the surface expression of AMPARs. Computing results of Asp-His-His-Cys (DHHC) 3, the main enzyme for palmitoylation of AMPARs, indicated that only the alkyl mercaptans with chain-like configuration, such as DTT and β-ME, can enter the pocket of DHHC3 and disrupt the catalytic activity via inhibiting DHHC3 auto-palmitoylation. Collectively, our findings indicate a novel redox-independent mechanism underlay the multiple effects of thiol reductants on synaptic function.