Figure 2.

Hypothetical model detailing mechanisms involved in cargo-specific endocytic sorting of SV proteins. Upon the arrival of an action potential at the nerve terminal SVs fuse with the presynaptic membrane via a SNARE-dependent mechanism. As a result cis-SNARE complexes comprising synaptobrevin 2, syntaxin 1A and SNAP-25 remain on the plasma membrane. For new rounds of exocytosis, cis-SNARE complex are disassembled via NSF with its cofactor α-SNAP, releasing free synaptobrevin 2 molecules. Endocytic sorting of SV proteins on the plasma membrane requires dedicated endocytic adaptors: vGLUT1 recognition by AP2 and endophilin,²⁰ synaptobrevin 2 binding to AP180 and CALM,¹² and synaptotagmin 1 sorting by AP2 and stonin 2.¹⁷–¹⁹ AP180 and CALM directly recognize the SNARE motif of synaptobrevin 2, perhaps to ensure that only free rather than SNARE-complexed synaptobrevin 2 is endocytically resorted to while syntaxin 1A and SNAP-25 are left behind. Recycling of synaptobrevin 2 has been shown to require synaptophysin although the molecular details of this mechanism remain unknown.²⁸ SV cargo becomes concentrated in clathrin-coated pits containing clathrin, endocytic adaptors and accessory proteins resulting in SV reformation. SV, synaptic vesicle; SytI, Synaptotagmin 1; vGLUT 1, vesicular glutamate transporter 1; Syp, synaptophysin; Syb2, synaptobrevin 2; NSF, N-ethylmaleimide-sensitive factor; α-SNAP, soluble NSF attachment proteins; mHD, µ homology domain; SHD, stonin homology domain.