The AMPAR lifecycle begins in the ER through the sequential assembly of homodimers or heterodimers followed by the dimerization of dimers. Tetramers are subsequently

exported from the ER and passed through the Golgi network, during which they are subjected to posttranslational modification in the form of phosphorylation and glycosylation (Greger et al., 2007 and Ziff, 2007). From early work on stargazin, it was unclear whether the lack of surface and synaptic AMPARs observed Enzalutamide in stargazer CGNs ( Chen et al., 2000) could be attributable to a role for stargazin as a chaperone during these early biosynthetic events, specific effects on surface expression and synaptic targeting of AMPARs, or both. In stargazer CGNs, despite only a minor reduction in total GluA2 protein in whole cerebella, GluA2 surface expression is dramatically reduced. A large proportion of the remaining GluA2 exhibits immature ER-type glycosylation, implying that click here GluA2 is unable to exit the ER and fully mature in stargazer CGNs. This result suggested that stargazin is involved in the early stages of GluA biosynthesis ( Tomita et al., 2003). In fact,

previous work showed that the majority of GluA protein, expressed in heterologous cells in the absence of TARPs, is also incompletely glycosylated and accumulates in intracellular pools, presumably corresponding to the ER ( Hall et al., 1997). Fluorescence resonance energy transfer (FRET) experiments suggested that TARPs may facilitate ER export by blocking ER-retention

sites on the AMPAR ( Bedoukian et al., 2006), although later work demonstrates that the stargazin CTD contains a region that is essential for forward traffic through the ER and Golgi. Furthermore, the stargazin CTD can be tacked onto unrelated receptors, and not only mediates their ER export, but directs their localization to specific membrane compartments ( Bedoukian et al., too 2008). Additional evidence that stargazin has a role to play in AMPAR biosynthesis and ER export are experiments showing that induction of the unfolded protein response (UPR), a homeostatic response to the accumulation of unfolded or misassembled protein in the ER, can boost GluA1 surface expression in heterologous cells in a way that mimics and occludes the effect of stargazin. In addition, stargazer CGNs exhibit enhanced UPR, compatible with the notion that, in the absence of stagazin, AMPAR subunits may be incompletely folded or assembled and stuck in the ER ( Vandenberghe et al., 2005b). Consistent with stargazin being exclusively associated with tetrameric AMPARs ( Vandenberghe et al., 2005a and Shanks et al., 2010), TARPs are likely to be incorporated into nascent AMPAR complexes at some point between tetramerization and ER export. The role that TARPs play, if any, in protein folding, RNA editing, and subunit assembly at an earlier stage in AMPAR biogenesis remains to be determined.