AP180 and CALM: Dedicated endocytic adaptors for the retrieval of synaptobrevin 2 at synapses

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.