Nitrosylation Promotes AMPA Receptor Phosphorylation

Sci. Signal.  22 Jan 2013:
Vol. 6, Issue 259, pp. ec22
DOI: 10.1126/scisignal.2003983

Regulation of activity-dependent responsiveness in glutamatergic synapses involves NMDA and AMPA glutamate receptors. Stimulation of NMDA receptors leads to the phosphorylation of the GluA1 subunit of the AMPA receptor and increased channel conductance and increased endocytosis of the receptors. Activation of NMDA receptors also stimulates the production of nitric oxide (NO), which has many roles in the regulation of synaptic activity. Selvakumar et al. showed in transfected HEK293 cells and in primary neuronal cultures that the phosphorylation of GluA1 at Ser831 was enhanced by NO, an effect that depended on NO modification primarily of Cys875. Single-channel analysis of HEK293 cells [expressing neuronal nitric oxide synthase, GluA1 or GluA1 C875A (both GluA1 subunits also had a mutation that limited receptor desensitization), and the intracellular AMPA receptor binding protein stargazing] showed that the GluA1 C875A mutant channels were less responsive to the presence of calcium-calmodulin kinase II and that the mutant channels had reduced basal conductance. Endocytosis experiments performed with hippocampal cultures expressing a fluorescent protein-tagged form of GluA1 or GluA1 C875A showed that NMDA failed to stimulate endocytosis of the mutant receptor subunit and coimmunoprecipitation experiments indicated that the interaction with the endocytotic clathrin adaptor protein AP2 was compromised in the mutant GluA1. Thus, S-nitrosylation of the GluA1 subunit contributes to the activity-dependent regulation of phosphorylation and trafficking of AMPA receptors.

B. Selvakumar, M. A. Jenkins, N. K. Hussain, R. L. Huganir, S. F. Traynelis, S. H. Snyder, S-nitrosylation of AMPA receptor GluA1 regulates phosphorylation, single-channel conductance, and endocytosis. Proc. Natl. Acad. Sci. U.S.A. 110, 1077–1082 (2013). [Abstract] [Full Text]