The neural cell adhesion molecule NCAM promotes maturation of the presynaptic endocytic machinery by switching synaptic vesicle recycling from AP3- to AP2- dependent mechanism in mice (Mus musculus, strain
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چکیده
Zusammenfassung I. Abstract/Zusammenfassung The neural cell adhesion molecule NCAM promotes maturation of the presynaptic endocytotic machinery by switching synaptic vesicle recycling from AP3 to AP2-dependent mechanisms Newly formed synapses undergo maturation during ontogenetic development via mechanisms that remain poorly understood. We show that maturation of the presynaptic endocytic machinery in central nervous system neurons requires substitution of the adaptor protein 3 (AP3) with AP2 at the presynaptic plasma membrane. In mature synapses, AP2 associates with the intracellular domain of the neural cell adhesion molecule NCAM. NCAM promotes binding of AP2 over binding of AP3 to presynaptic membranes, thus favoring the substitution of AP3 for AP2 during formation of mature synapses. The presynaptic endocytotic machinery remains immature in adult NCAM-deficient mice accumulating AP3 instead of AP2 in synaptic membranes and vesicles. NCAM deficiency or disruption of the NCAM/AP2 complex in NCAM+/+ neurons by transfection with a dominant-negative NCAM containing the mutated AP2 binding site leads to less efficient endocytosis of synaptic vesicle membranes. Abnormalities in synaptic vesicle endocytosis and recycling may thus contribute to neurological disorders associated with mutations in NCAM.
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