Synaptic vesicles that store monoamines and glutamate differ in protein composition

Neuromodulators such as monoamines assure essential brain functions, but relatively little is known about their mechanism of release. While recent work has advanced our knowledge of active zone architecture in dopamine axons, release machinery within the synaptic vesicle (SV) remains poorly understood. Here, we address differences between the release of monoamines and synaptic transmitters by comparing the composition of SVs that contain the vesicular monoamine transporter 2 (VMAT2) versus vesicular glutamate transporter 2 (VGLUT2). Previous work revealed that these SVs differ in frequency dependence, recycling kinetics, and biogenesis. We now find differences in the abundance and isoform expression of many SV protein families and validate these differences in primary neurons and brain tissue. Functional analysis after heterologous expression in hippocampal neurons shows that loss of differentially expressed SCAMP5 selectively impairs the recycling of VGLUT2 SVs, sparing vesicles targeted by VMAT2 in the same neuronal population. These findings provide insights into the molecular diversity of SVs and mechanisms of dopamine release.