How does CNIH-2/-3 control the level of AMPARs on the surface of hippocampal pyramidal neurons? One possibility is that in the absence of CNIH-2/-3 AMPAR protein is lost, similar to what is seen in γ-8 KO mice (Rouach et al., 2005). However, the modest loss of AMPAR protein seen in the NexCnih2−/− mice cannot explain the profound loss of surface AMPARs. Rather our data suggest that the maturation of AMPARs is impaired and that the immature receptors are retained in the ER/cis-Golgi. As pointed out previously (Shi et al, 2009), such a role is remarkably similar to the established role of the yeast (Erv14p) and Drosophila (Cni) CNIH homologues, in which these proteins serve as chaperones that aid in the forward trafficking of EGFR ligands from the ER to Golgi (Bokel et al., 2006; Castillon et al., 2009; Roth et al., 1995). However, unlike the yeast and Drosophia homologues, but analogous to its effects in HEK cells, CNIH-2 can remain associated with neuronal AMPARs, at least in the absence of γ-8 protein.
