Communication between neurons largely occurs at chemical synapses by conversion of electric to chemical signals. Chemical neurotransmission involves the action potential-driven release of
neurotransmitters from synaptic vesicles (SVs) at presynaptic nerve terminals. Fusion of SVs is driven by SNARE complex formation comprising
synaptobrevin 2 on the SV membrane and
syntaxin 1A and SNAP-25 on the plasma membrane. In order to maintain neurotransmission during repetitive stimulation and to prevent expansion of the presynaptic plasma membrane, exocytic SV fusion needs to be balanced by compensatory retrieval of SV components to regenerate functional vesicles. Our recent work has unraveled a mechanism by which the R-SNARE
synaptobrevin 2, the most abundant SV
protein and an essential player for exocytic fusion, is recycled from the presynaptic membrane. The SNARE motif of
synaptobrevin 2 is directly recognized by the ANTH domains of AP180 and CALM, monomeric endocytic adaptors for
clathrin-mediated endocytosis. Given that key residues involved in
synaptobrevin 2-ANTH domain complex formation are also essential for SNARE assembly, we propose that disassembly of SNARE complexes is a prerequisite for
synaptobrevin 2 retrieval, thereby preventing endocytic mis-sorting of the plasma membrane
Q-SNAREs syntaxin 1A and SNAP-25. It is tempting to speculate that perturbed
synaptobrevin 2 recycling caused by reduction of CALM or AP180 levels may lead to disease as suggested by the genetic association of ANTH domain
proteins with
neurodegenerative disorders.