AMPA-type glutamate receptors (AMPARs) are the principal receptors that mediate fast excitatory synaptic transmission in the brain. Their trafficking and functional properties depend critically on their association with transmembrane AMPAR regulatory proteins (TARPs). Six functional TARP family members have been identified and classified as type I (γ-2, -3, -4 and -8) or type II (γ-5 and -7). Type I TARPs promote AMPAR surface expression and synaptic trafficking (Tomita et al, 2003). The properties of type II TARPs are less clear but they regulate predominantly calcium-permeable AMPARs (CP-AMPARs) (Soto et al, 2009; Studniarczyk et al, 2013). In addition, γ-5 appears unique amongst TARPs, in that it differentially modifies the channel properties of AMPAR subtypes based on the length of their C-tail and reduces AMPAR surface trafficking (Soto et al, 2009). We used confocal fluorescence imaging to investigate the subcellular distribution of YFP-γ-5 expressed in HEK293 cells and cultured cerebellar granule cells from C57BL/6 mice. Unlike γ-2 and γ-7, the majority of γ-5 did not localize in the plasma membrane, but rather in intracellular puncta (observed in >20 cells in each of 4 cultures). γ-5 colocalization with CD-63 indicated that the puncta were late endosomes and lysosomes, and hence that γ-5 is trafficked to the cell’s degradative pathways (>30 cells from 10 cultures). By examining fluorescent chimeric constructs of γ-5 and γ-7 we found that, as with the type I TARPs (Tomita et al, 2005), its intracellular C-tail region dictated the trafficking. Specifically the distal C-terminus was critical in determining γ-5 distribution (>20 cells from 3 cultures). Experiments using point mutations ruled out a role for monoubiquitination (>50 cells from 2 cultures) or for the YXXM AP-3 trafficking motif (>50 cells from 2 cultures). While ablation of γ-5’s PDZ-binding domain did not affect lysosomal trafficking, replacement of its PDZ-binding domain (SSPC) by one that corresponded to the conventional class 1 PDZ-binding domain of type I TARPs (TTPV), led to increased surface trafficking (>50 cells from 3 cultures). Finally, mutation of Ser271 (a site adjacent to the PDZ binding domain) increased the trafficking of γ-5 to the cell surface (>40 cells from 3 cultures). Our data are consistent with a model whereby γ-5-associated AMPARs are constitutively trafficked to degradation pathways. This behaviour appears to be determined, at least in part, by the C-terminal PDZ-binding domain of the TARP.