The co-transmission of neuropeptides and small-molecule transmitters for the activation of metabotropic and ionotropic receptors, respectively, are central to the regulation of synapse circuits. The transmitter classes have different locations and mechanisms for vesicular packaging: neuropeptides are packaged in the dense-core vesicles (DCVs) before being transported to the synapse and small-molecule transmitters are packaged at synapses; an example is monoamine, which is packaged by the vesicular monoamine transporter (VMAT). Given these spatial presynaptic differences, co-release appears to be the sole means of controlling co-transmission. In their Research Article, Edwin Levitan and colleagues (Tao et al., 2019) demonstrate that loss of the Drosophila receptor protein tyrosine phosphatase (Rptp) PtP4E leads to a simultaneous increase of neuropeptides and small-molecule transmitters. The authors show, using confocal, electron and super-resolution microscopy, that DCV size and neurotransmitter release efficiency or transport are not altered upon PtP4E deficiency. In the same synaptic boutons, monoamine packaging for its synaptic release is controlled by VMATs, with enhanced VMAT activity in absence of PtP4E. Likewise, neuropeptide packaging at the level of single DCVs is increased. Thus, the Rptp PtP4E regulates scaling of packaging mechanisms for neuropeptides and small-molecule transmitter co-transmission in neurons.