ABSTRACT
Many neurons influence their targets through co-release of neuropeptides and small-molecule transmitters. Neuropeptides are packaged into dense-core vesicles (DCVs) in the soma and then transported to synapses, while small-molecule transmitters such as monoamines are packaged by vesicular transporters that function at synapses. These separate packaging mechanisms point to activity, by inducing co-release as the sole scaler of co-transmission. Based on screening in Drosophila for increased presynaptic neuropeptides, the receptor protein tyrosine phosphatase (Rptp) Ptp4E was found to post-transcriptionally regulate neuropeptide content in single DCVs at octopamine synapses. This occurs without changing neuropeptide release efficiency, transport and DCV size measured by both stimulated emission depletion super-resolution and transmission electron microscopy. Ptp4E also controls the presynaptic abundance and activity of the vesicular monoamine transporter (VMAT), which packages monoamine transmitters for synaptic release. Thus, rather than rely on altering electrical activity, the Rptp regulates packaging underlying monoamine-neuropeptide co-transmission by controlling vesicular membrane transporter and luminal neuropeptide content.
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Footnotes
Author contributions
Conceptualization: J.T., D.L.D., E.S.L.; Methodology: J.T., D.B., D.L.D., E.S.L.; Validation: J.T., D.A.B.; Formal analysis: J.T., D.B., D.A.B., N.S., E.S.L.; Investigation: J.T., D.B., D.A.B., M.J.C., H.J.F.V., N.S.; Resources: S.C.W., N.S., D.L.D.; Writing - original draft: E.S.L.; Writing - review & editing: J.T., D.B., N.S., D.L.D.; Supervision: E.S.L.; Project administration: E.S.L.; Funding acquisition: E.S.L.
Funding
This study was supported by the National Institute of Neurological Disorders and Stroke [NS032385 to E.S.L.] and the National Institutes of Health [S10OD021540 to S.C.W.]. Deposited in PMC for release after 12 months.
