Identifying the function of the NMDA NR1 ^C2 subunit through its interaction with Magi-2 during inflammatory pain

Much is understood about the structure and gating properties of NMDA receptors (NMDAR), but the function of the carboxy-terminal splice variant of the NR1 subunit, NR1 ^C2 has never been identified. By studying the scaffolding protein Magi-2 in animal models of inflammatory pain, we discovered how NR1 ^C2 protein is specifically regulated. We found that Magi-2 deficiency resulted in decreased pain behavior and a concomitant reduction in NR1 ^C2 protein. Magi-2 contains WW domains, domains typically found in ubiquitin ligases. We identified an atypical WW-binding domain within NR1 ^C2 which conferred susceptibility to Nedd4-1 ubiquitin-ligase dependent degradation. We used lipidated peptidomimetics derived from the NR1 ^C2 sequence and found that NR1 ^C2 protein levels and pain behavior can be pharmacologically targeted. The function of NR1 ^C2 is to give lability to a pool of NMDAR, important for pain signaling.