SAP97 has been shown to regulate NMDA receptors having NR1-1, an NR1 splice variant, into a non-conventional dendritic secretory pathway which has local dendritic delivery characteristics. Another protein called CASK is also required for sorting into the dendritic secretory pathway, and evidence in heterologous cells suggests both SAP97 and CASK are also the keys to ER exit. The same subunit combination, NR1-1/NR2, remains ER-retained with only SAP97 in co-transfected HEK293 cells. ER retention of this complex in HEK293 cells can be overcome by co-expression of exogenous CASK. Thus, both SAP97 and CASK are dually required for sorting NR1-1 containing receptors into the dendritic secretory pathway, and required for ER exit of those same receptors. The mechanism that blocks ER retention to link NMDA receptors to the non-conventional secretory pathway remains to be determined. On the other hand, we show that SAP97 blocks ER retention of NR1 splice variant, NR1-3, in a CASK- independent way; SAP97 does so by sterically blocking the NR1-3 RXR-based ER retention signal with its SRC Homology 3 (SH3) domain. Thus, SAP97 exhibits an NMDA receptor subunit-dependent differential interaction that in one case requires CASK for ER exit, and in another, jettisons the subunit with no other requirement. Based on the evidence, we hypothesize the C-termini of NR1-1 and NR1-3, coupled with SAP97, form a binary sorting switch at the level of the ER, sorting either into a conventional (NR1-3), or non-conventional CASK-dependent dendritic secretory pathway (NR1-1). SAP97 sorting into these alternative secretory pathways may have important implications for schizophrenia, since the expression of these forms is altered in schizophrenics.
