This indicates that in worms autophagy represents a pathway

for endocytic lysosomal degradation of GABAARs ( Rowland et al., 2006). Third, GABARAP knockout mice show normal expression and punctate distribution of γ2-containing GABAARs ( O’Sullivan et al., 2005), possibly due to functional redundancy of GABARAP with GEC1 ( Mansuy-Schlick et al., 2006) and other GABARAP family members. Fourth, the function of GABARAP is complicated by its interactions with a very large number of other proteins. Among these the ER luminal Ca2+-dependent chaperone calreticulin stands out in that it binds GABARAP with exceptionally high affinity ( Mohrlüder et al., 2007). Compared to calreticulin the interaction GSK2656157 cost of GABARAP with γ2-derived peptides shows low affinity, suggesting that GABARAP might promote protein trafficking unspecifically along the secretory pathway ( Knight et al., 2002). Several GABARAP-interacting proteins contribute to GABAAR trafficking independently of GABARAP. The aforementioned NMDAR-induced and GABARAP-dependent Ferroptosis inhibitor increase in GABAAR clustering also depends on the synaptic PDZ domain-containing protein GRIP (Marsden et al., 2007), which interacts with GABARAP in vitro and in vivo (Kittler et al., 2004a). GRIP was first described as a trafficking factor of AMPARs (Dong

et al., 1997). It is present at both glutamatergic and GABAergic synapses, consistent with functions at both types of synapses (Dong et al., 1999, Charych et al., 2004a, Kittler et al., 2004a and Li et al., 2005). GABARAP further interacts with the phospholipase C-related catalytically inactive proteins 1 and 2 (PRIP1/2, PRIP1 was previously named p130; Kanematsu et al., 2002), a pair of GABAAR-associated adaptor proteins for phosphatases and kinases (Figure 3A)

(Kanematsu et al., 2002 and Uji et al., 2002). Likewise, GABARAP and its paralog GATE-16 (Sagiv et al., 2000) interact with NSF, an ATPase and chaperone of SNARE complexes that is critically important for regulated neurotransmitter release and also involved in trafficking of neurotransmitter receptors (Morgan and Burgoyne, 2004 and Zhao Adenosine et al., 2007). Both PRIP1/2 and NSF interact with GABAARs indirectly through GABARAP and directly via GABAAR β subunits (Figure 1C) (Kanematsu et al., 2002, Kittler et al., 2004a, Terunuma et al., 2004 and Goto et al., 2005). PRIP1/2 double knockout mice exhibit reduced expression and altered behavioral pharmacology of GABAARs, suggesting deficits in mainly γ2-containing GABAARs (Kanematsu et al., 2002, Kanematsu et al., 2006 and Mizokami et al., 2007). Brain extracts of these mice further show reduced association of GABAARs with GABARAP, indicating that PRIP facilitates indirect association of GABARAP with GABAARs (Mizokami et al., 2007). Moreover, PRIP and the γ2 subunit compete for binding to the same binding site on GABARAP (Kanematsu et al., 2002 and Uji et al., 2002).