Neuronal and non-neuronal functions of the AP-3 sorting machinery

Abstract

Vesicles selectively exchange lipids, membrane proteins and luminal contents between organelles along the exocytic and endocytic routes. The repertoire of membrane proteins present in these vesicles is crucial for their targeting and function. Vesicle composition is determined at the time of their biogenesis by cytosolic coats. The heterotetrameric protein adaptor protein complex 3 (AP-3), a coat component, participates in the generation of a diverse group of secretory organelles and lysosome-related organelles. Recent work has shed light on the mechanisms that regulate AP-3 and the trafficking pathways controlled by this adaptor. Phenotypic analysis of organisms carrying genetic deficiencies in the AP-3 pathway highlight its role regulating the targeting of lysosomal, melanosomal and synaptic vesicle-specific membrane proteins. Synaptic vesicles from AP-3-deficient mice possess altered levels of neurotransmitter and ion transporters, molecules that ultimately define the type and amount of neurotransmitter stored in these vesicles. These findings reveal a complex picture of how AP-3 functions in multiple tissues, including neuronal tissue, and expose potential links between endocytic sorting mechanisms and the pathogenesis of psychiatric disorders such as schizophrenia.

Evidence That the BLOC-1 Protein Dysbindin Modulates Dopamine D2Receptor Internalization and Signaling But Not D1Internalization

“…The specific mechanism by which a deficiency in BLOC-1 proteins might modulate DRD2 is unclear, but is likely to be attributable to the fact that internalized DRD2 is subject to degradation via an endosomal-lysosomal pathway, whereas most DRD1 is recycled to the plasma membrane (Bartlett et al, 2005;Martin-Negrier et al, 2006). This role in differential trafficking would also be consistent with recent work showing that BLOC-1 interacts with two other complexes, AP-3 and BLOC-2, and traffics lysosome-associated membrane proteins from the early endosome to the late endosome, to lysosomes, and to the trans-Golgi network (for review, see Newell-Litwa et al, 2007;Setty et al, 2007).…”

Drosophila Crumbs prevents ectopic Notch activation in developing wings by inhibiting ligand-independent endocytosis

“…g is the Drosophila homolog of the human AP-3 complex member AP-3δ . The AP-3 complex is required for selective transport to the lysosome (Cowles et al, 1997;Dell'Angelica et al, 1997;Newell-Litwa et al, 2007). Reduction of car or g function in an otherwise wild-type background using hypomorphic alleles car 1 and g 1 had no effect on the formation of L5 (Fig.…”

Formation and function of Weibel-Palade bodies

“…3). AP3 is an adaptor involved in targeting of proteins from early endosomes to lysosomes and lysosome-related organelles (reviewed by Raposo et al, 2007;Robinson and Bonifacino, 2001) as well as synaptic vesicles (Newell-Litwa et al, 2007). The presence of CD63 within the membrane of WPBs and their ability to recruit components after budding from the TGN suggest that WPBs may be regarded as lysosome-related secretory organelles, although the primary role of VWF in driving their formation at the TGN might justify classifying them as also being close to classical secretory granules.…”