SNAP-25, a Known Presynaptic Protein with Emerging Postsynaptic Functions

Abstract

A hallmark of synaptic specializations is their dependence on highly organized complexes of proteins that interact with each other. The loss or modification of key synaptic proteins directly affects the properties of such networks, ultimately impacting synaptic function. SNAP-25 is a component of the SNARE complex, which is central to synaptic vesicle exocytosis, and, by directly interacting with different calcium channels subunits, it negatively modulates neuronal voltage-gated calcium channels, thus regulating intracellular calcium dynamics. The SNAP-25 gene has been associated with distinct brain diseases, including Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia and bipolar disorder, indicating that the protein may act as a shared biological substrate among different "synaptopathies". The mechanisms by which alterations in SNAP-25 may concur to these psychiatric diseases are still undefined, although alterations in neurotransmitter release have been indicated as potential causative processes. This review summarizes recent work showing that SNAP-25 not only controls exo/endocytic processes at the presynaptic terminal, but also regulates postsynaptic receptor trafficking, spine morphogenesis, and plasticity, thus opening the possibility that SNAP-25 defects may contribute to psychiatric diseases by impacting not only presynaptic but also postsynaptic functions.

Keywords: SNAP-25; brain diseases; postsynaptic role; presynaptic role; synaptopathies.

Figure 1

Cartoon depicting presynaptic and postsynaptic roles of SNAP-25. (A) Effect of presynaptic SNAP-25 on VGCCs. Calcium influx in the nerve terminal is negatively regulated by the complex formation between SNAP-25 and VGCCs; removal of the clamping role of SNAP-25, occurring upon reduction of the protein expression, results in elevated calcium influx through VGCCs (adapted from Kochlamazashvili and Haucke, 2013). (B) Involvement of SNAP-25 in the molecular machinery mediating Ca²⁺-triggered vesicle fusion. A docked synaptic vesicle is shown on the left. The core fusion machine is composed of synaptobrevin/VAMP2, syntaxin-1, and SNAP-25 (adapted from Kochlamazashvili and Haucke, 2013). The diagram in the box depicts a partially assembled SNARE complex including, besides synaptobrevin/VAMP2, syntaxin-1, and SNAP-25, complexins and MUNC18. The calcium sensor, synaptotagmin, is also depicted (adapted from Sudhof, 2012). (C) Role of SNAP-25 in slow clathrin-mediated synaptic vesicle endocytosis. SNAP-25 binds to the endocytic protein intersectin, while syntaxin binds dynamin, a GTPase mediating vesicle fission. The interactions between Synaptobrevin/VAMP2 and the ANTH domain of endocytic adaptors AP180 and CALM have been omitted for clarity. (D) Role of SNAP-25 in the organization of the postsynaptic density protein network. SNAP-25 interacts with p140Cap, which in turn forms a complex with PSD95, cortactin, Arp2,3, and F-actin (filamentous actin). NMDA receptors are depicted as interacting with PSD95 (adapted from Fossati et al., 2015). (E) Phosphorylation of SNAP-25 by PKC promotes the insertion of NMDA channels at the cell surface through the delivery of postsynaptic vesicles and their fusion with the plasma membrane, possibly via the formation of a SNARE complex (adapted from Lau et al., 2010). (F) Role of SNAP-25 in the removal of GluK5-contaning kainate receptors (KAR). KARs associate with SNAP-25 and the PKC-interacting protein PICK1. The PKC phosphorylation of the GluK5-C terminus may induce a conformational change facilitating the association with SNAP-25 and simultaneously decreasing GRIP binding affinity (adapted from Selak et al., 2009).