Mammalian vesicular glutamate transporter VGLUT1 reduces synaptic vesicle super-pool size and spontaneous release frequency

Abstract

Keywords: synaptic vesicle; synaptic vesicle super-pool; vesicular glutamate transport; liquid phase separation; EndophilinA1; quantal neurotransmitter release; fluorescence live cell microscopy; synaptic vesicle cycle. Zhang X.M. et al., 2018 2 ABSTRACTGlutamate secretion at excitatory synapses is tightly regulated to allow for the precise tuning of synaptic strength. Vesicular Glutamate Transporters (VGLUT) accumulate glutamate into synaptic vesicles (SV) and thereby regulate quantal size. Further, the number of release sites and the release probability of SVs maybe regulated by the organization of active zone proteins and SV clusters. In the present work, we uncover a mechanism mediating an increased SV clustering through a tripartite interaction of VGLUT1, endophilinA1 and intersectin1. This strengthening of SV clusters results in a combined reduction of axonal SV super-pool size and miniature excitatory events frequency. Our findings support a model in which clustered vesicles are held together through multiple weak interactions between SH3 domains and proline rich sequences of synaptic proteins. In mammals, VGLUT1 gained a poly-proline sequence that recruits endophilinA1 and turns the transporter into a dual regulator of quantal release parameters at excitatory synapses.

Molecular, Structural, Functional, and Pharmacological Sites for Vesicular Glutamate Transporter Regulation

“…Original findings revealed that a reduction of VGLUT1 expression results in the loss of synaptic vesicles in nerve terminals [115]. More recent studies indicate that synaptic vesicle clustering in VGLUT1 terminals is mediated through a tripartite interaction of VGLUT1, endophilinA1, and intersectin1 resulting in a combined reduction of axonal synaptic vesicle super-pool size and miniature excitatory events frequency [124,125]. Indeed, low glutamate release probability is a characteristic feature of VGLUT1-encoded synaptic terminals [126][127][128][129].…”