The neuronal form of adaptor protein-3 is required for synaptic vesicle formation from endosomes.
Heterotetrameric adaptor complexes vesiculate donor membranes. One of the adaptor protein complexes, AP-3, is present in two forms; one form is expressed in all tissues of the body, whereas the other is restricted to brain. Mice lacking both the ubiquitous and neuronal forms of AP-3 exhibit neurological disorders that are not observed in mice that are mutant only in the ubiquitous form. To begin to understand the role of neuronal AP-3 in neurological disease, we investigated its function in in vitro assays as well as its localization in neural tissue. In the presence of GTPgammaS both ubiquitous and neuronal forms of AP-3 can bind to purified synaptic vesicles. However, only the neuronal form of AP-3 can produce synaptic vesicles from endosomes in vitro. We also identified that the expression of neuronal AP-3 is limited to varicosities of neuronal-like processes and is expressed in most axons of the brain. Although the AP-2/clathrin pathway is the major route of vesicle production and the relatively minor neuronal AP-3 pathway is not necessary for viability, the absence of the latter could lead to the neurological abnormalities seen in mice lacking the expression of AP-3 in brain. In this study we have identified the first brain-specific function for a neuronal adaptor complex.
Blumstein
J
J
Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143-0448, USA.
Faundez
V
V
Nakatsu
F
F
Saito
T
T
Ohno
H
H
Kelly
R B
RB
D033942:Adaptor Proteins, Vesicular Transport; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001369:Axons / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D002352:Carrier Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D002474:Cell-Free System / Q000737:chemistry / Q000378:metabolism; D003600:Cytosol / Q000737:chemistry / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D034041:Monomeric Clathrin Assembly Proteins; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009928:Organ Specificity; D016716:PC12 Cells; D020033:Protein Isoforms / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D050683:R-SNARE Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D013572:Synaptic Vesicles / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D000906:Antibodies; D002352:Carrier Proteins; D008565:Membrane Proteins; D034041:Monomeric Clathrin Assembly Proteins; D020033:Protein Isoforms; D050683:R-SNARE Proteins; C439023:clathrin assembly protein AP180; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000255:Adenosine Triphosphate