Fig. 3. AP-3 sorting mechanisms in neuronal cells. A neuron possesses neuronal and ubiquitous AP-3 complexes in the cell body (a) but only neuronal AP-3 in axons (b) and dendrites (c) (Seong et al., 2005). (A) Proposed functions of the neuronal and ubiquitous AP-3 in cell bodies. Both AP-3 forms reside in the same endosome. Neuronal AP-3 sorts proteins into the axon or a synaptic vesicle pathway. Ubiquitous AP-3 sorts proteins to the lysosomal pathway. Model A explains the changes in ZnT3 levels observed in Ap3b1^–/– and Ap3b2^–/– mice (Seong et al., 2005). In this model AP-3-sorted proteins, like ZnT3, are recognized by both AP-3 isoforms and therefore routed to either a synaptic vesicle-axonal or a lysosomal pathway. Thus, in the absence of one AP-3 isoform, membrane proteins are targeted to the other pathway. The amount of ZnT3 in synaptic vesicles is reduced in the absence of neuronal AP-3 (Ap3b2^–/–) and ZnT3 is instead routed to lysosomes for degradation. Similarly, the amount of ZnT3 targeted to lysosomes is reduced in the absence of ubiquitous AP-3 (Ap3b1^–/–) and it is then routed by the neuronal AP-3 (encoded by Ap3b2) to synaptic vesicles, thus triggering increased levels of ZnT3 in synaptic vesicles. Model B shows the proposed role of neuronal AP-3 in synaptic vesicle biogenesis in presynaptic terminals. AP-3 generates synaptic vesicles from presynaptic endosomes. This route is parallel to the AP-2 route, which generates synaptic vesicles from the plasma membrane. A role for AP-3 in sorting to dendrites (c) has not been documented yet.