Molecular Signatures Underlying Synaptic Vesicle Cargo Retrieval

Abstract

Efficient retrieval of the synaptic vesicle (SV) membrane from the presynaptic plasma membrane, a process called endocytosis, is crucial for the fidelity of neurotransmission, particularly during sustained neural activity. Although multiple modes of endocytosis have been identified, it is clear that the efficient retrieval of the major SV cargos into newly formed SVs during any of these modes is fundamental for synaptic transmission. It is currently believed that SVs are eventually reformed via a clathrin-dependent pathway. Various adaptor proteins recognize SV cargos and link them to clathrin, ensuring the efficient retrieval of the cargos into newly formed SVs. Here, we summarize our current knowledge of the molecular signatures within individual SV cargos that underlie efficient retrieval into SV membranes, as well as discuss possible contributions of the mechanisms under physiological conditions.

Keywords: clathrin; endocytic motif; endocytosis; pHluorin; synaptic vesicles.

Figure 1

Retrieval mechanisms of SV cargos. (A) Di-leucine motif. AP-2 recognizes a di-leucine or a dileucine-like motif within the cytoplasmic region of SV cargos (e.g., VGLUT and VGAT). AP-2/cargo protein complexes are incorporated into SV surrounded by clathrin complexes. (B) C2 domain. The basic motif within the C2 domains of Syt 1 is required for binding of AP-2, and the binding is enhanced by a tyrosine-based motif of SV2A. (C) SNARE motif. The SNARE motif of Syb2 binds to the ANTH domain of AP180/CALM, which recruits clathrin complexes. (D) Proline-rich domain. The proline-rich domain of VGLUT1 interacts with a SH3 domain of endophilin, which senses membrane curvature and recruits dynamin that mediates membrane tubulation and fission. (E) Cargo–cargo interaction. (Left panel) Syp and Syb2 form a 1:2 complex on SVs, and the complex is dissociated upon SNARE complex assembly during exocytosis. After exocytosis, the Syp/Syb2 complex is reformed and incorporated into SV. (Right panel) In the absence of Syp, the efficiency of Syb2 retrieval would be decreased.