title: The neural cell adhesion molecule promotes maturation of the presynaptic endocytotic machinery by switching synaptic vesicle recycling from adaptor protein 3 (AP-3)- to AP-2-dependent mechanisms.
abstract: Newly formed synapses undergo maturation during ontogenetic development via mechanisms that remain poorly understood. We show that maturation of the presynaptic endocytotic machinery in CNS neurons requires substitution of the adaptor protein 3 (AP-3) with AP-2 at the presynaptic plasma membrane. In mature synapses, AP-2 associates with the intracellular domain of the neural cell adhesion molecule (NCAM). NCAM promotes binding of AP-2 over binding of AP-3 to presynaptic membranes, thus favoring the substitution of AP-3 for AP-2 during formation of mature synapses. The presynaptic endocytotic machinery remains immature in adult NCAM-deficient (NCAM-/-) mice accumulating AP-3 instead of AP-2 and its partner protein AP180 in synaptic membranes and vesicles. NCAM deficiency or disruption of the NCAM/AP-2 complex in wild-type (NCAM+/+) neurons by overexpression of AP-2 binding-defective mutant NCAM interferes with efficient retrieval of the synaptic vesicle v-SNARE synaptobrevin 2. Abnormalities in synaptic vesicle endocytosis and recycling may thus contribute to neurological disorders associated with mutations in NCAM.
authors.affiliation: Zentrum für Molekulare Neurobiologie, Universität Hamburg, 20246 Hamburg, Germany, School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, New South Wales 2052, Australia, Leibniz Institut für Molekulare Pharmakologie and Freie Universität Berlin, 13125 Berlin, Germany, Keck Center for Collaborative Neuroscience, Rutgers University, Piscataway, New Jersey 08854-8082, and Center for Neuroscience, Shantou University Medical College, Shantou 515041, People's Republic of China.
authors.forename: Aparna
authors.initials: A
authors.lastname: Shetty
authors.forename: Vladimir
authors.initials: V
authors.lastname: Sytnyk
authors.forename: Iryna
authors.initials: I
authors.lastname: Leshchyns'ka
authors.forename: Dmytro
authors.initials: D
authors.lastname: Puchkov
authors.forename: Volker
authors.initials: V
authors.lastname: Haucke
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
mesh_terms: D033962:Adaptor Protein Complex 2 / Q000235:genetics / Q000378:metabolism*; D033963:Adaptor Protein Complex 3 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004705:Endocytosis / Q000502:physiology*; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism*; D013570:Synaptic Membranes / Q000378:metabolism; D013572:Synaptic Vesicles / Q000235:genetics / Q000378:metabolism*; D050988:Vesicle-Associated Membrane Protein 2 / Q000235:genetics / Q000378:metabolism
chemical_list: D033962:Adaptor Protein Complex 2; D033963:Adaptor Protein Complex 3; D019006:Neural Cell Adhesion Molecules; D050988:Vesicle-Associated Membrane Protein 2