FIGURE 3.

Protein S-nitrosylation regulates glutamatergic signaling contributing to hyperexcitability in AD. Excessive production of NO-related species due to hyperactivation of NMDA-type glutamate receptors results in S-nitrosylation (SNO) of multiple proteins. These include several proteins involved in glutamate release and re-uptake as well as AMPA receptor trafficking. For example, in addition to regulating NMDA receptor activity (see Figure 2), NO-mediated S-nitrosylation can regulate glutamatergic signaling via (i) vesicular glutamate transporter 1 (VGLUT1) involved in glutamate release, (ii) glutamate transporter-1 (GLT-1)/excitatory amino-acid transporter 2 (EAAT2) involved in glutamate clearance, and (iii) AMPA receptor subunits (e.g., GluA1) as well as AMPA receptor-associated proteins, such as stargazin, N-ethylmaleimide sensitive factor (NSF), and Thorase, involved in AMPA receptor recycling. Dysfunction in glutamate signaling can contribute to hyperexcitability and impaired synaptic plasticity in AD and other neurological conditions.