Mechanisms of Septin-mediated Inhibition of Neurotransmitter Release

Neurons communicate at chemical synapses via exocytosis of synaptic vesicles containing neurotransmitter, a process mediated by SNARE proteins. SEPT5, a predominantly brainspecific member of the septin family of GDP/GTP-binding cytoskeletal proteins, binds the SNARE STX1A. Furthermore, SEPT5 inhibits exocytosis and has been implicated in the organization of synaptic vesicles within the presynaptic active zone. However, a mechanism underlying the inhibition of exocytosis by SEPT5 is unknown. Using pull-down and yeast twohybrid assays, the current study further characterized the SEPT5-STX1A interaction. Binding of STX1A required SEPT5 to be GDP-bound and occurred via a region of SEPT5 encompassing a sequence similar to the SNARE VAMP2. Furthermore, an interaction between the STX1A binding partner Munc18-1 and SEPT3 indicates that the SEPT5-STX1A interaction may be part of a larger septin-STX1A-Munc18-1 complex. This study thereby advances understanding of potential mechanisms regulating the organization of synaptic vesicles and exocytosis of