FIGURE 8.

Putative model illustrating PDZ cargo-determined function of PICK1 in regulating trafficking of its binding partners. a, PICK1 PDZ binding partners (“PDZ cargo”), such as the DAT and agonist-internalized GPR10 as well as the DOR engineered to bind PICK1 (DOR DAT8), are sorted upon internalization primarily to late endosomes and subsequently to lysosomal degradation. In contrast, PICK1 PDZ binding partners, such as constitutively internalized GPR10 and AMPAR as well as β₂AR engineered to bind PICK1 (β₂DAT8), are sorted to the Rab11-dependent long loop recycling pathway. b, PICK1 will be recruited to the plasma membrane by its different PDZ cargos independently of their postendocytic sorting pattern. At the plasma membrane, PICK1 might serve a variety of different functions in relation to these cargos including e.g. bringing PKCα in close proximity to regulate their phosphorylation or bind other PDZ cargos. Our data provide no evidence that PICK1 affects internalization of its PDZ cargo, and our data do not provide any evidence that PICK1 acts as a sorting module and thus affects their postendocytic sorting pattern. Also, our data suggest that PICK1 does not reside by itself in any recycling pathway but is brought there by its cargo. Thus, the role of PICK1 in regulating recycling might be explained simply by a stabilization of PICK1 in complex with its PDZ cargo in a Rab11-positive recycling compartment in a BAR domain-dependent fashion. According to the previously proposed autoinhibition hypothesis for the PICK1 BAR domain, this recruitment to a membrane compartment by its cargo would unmask the membrane binding capacity of the BAR domain, leading to clustering of PICK1 with its cargo. In this way, PICK1 might function as a compartment-specific anchor only activated by interaction partners sorted to Rab11-dependent recycling. It is possible that this function also involves other proteins, such as the small GTPases ARF1/3 or neuronal calcium sensor 1 (NCS1), and/or direct interaction with actin filaments, but further studies are required to clarify this issue. Finally, it should be considered that via the lipid deforming capacity of the BAR domain, PICK1 once brought to the recycling endosomes and activated might also be capable of affecting the shape of the membranes, thereby affecting fusion or fission events in this compartment in general.