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Loh et al. Extracell Vesicles Circ Nucleic Acids 2023;4:568-87 https://dx.doi.org/10.20517/evcna.2023.34 Page 570

Figure 1. Secretory pathways in (neuro)endocrine cells. In endocrine cells and neurons, peptide hormones, neuropeptides, trophic
factors, and granins are sorted at the TGN into immature vesicles that then mature to become DCV. Their content is released via the
RSP upon stimulation. Other proteins in the Golgi complex are packaged into constitutive vesicles and secreted via the CSP, a default
pathway. sEVs originate from ILVs formed through either endocytic pathway or possibly ER/Golgi secretory pathway. They are then
taken up by MVBs. When the MVBs fuse with the plasma membrane, the sEVs are released. TGN: trans-Golgi network; DCV: dense
core vesicles; RSP: regulated secretory pathway; CSP: constitutive secretory pathway; sEVs: small extracellular vesicles; ILVs:
intraluminal vesicles; ER: endoplasmic reticulum; MVBs: multivesicular bodies.

DCVs are 100-200 nm in size, whereas the constitutive vesicles are smaller (40-100 nm). The content of the
DCVs is released by exocytosis to the extracellular space, and the secreted molecules exert their effects by
binding to classical receptors or membrane protein-binding partners for receptor activation and
downstream signaling. In endocrine cells, released hormones can be blood-borne and exert their effects by
binding to receptors at some distance away from the release site. Conversely, in the nervous system,
neurotrophic factors are released from RSP vesicles into the synaptic cleft, close to the proximity of the
receptors on the post-synaptic terminals for their action. Recently, it has been found that neuroendocrine
cells secrete sEVs. sEVs originate from intraluminal vesicles (ILVs) formed through either endocytic
pathway or possibly endoplasmic reticulum (ER)/Golgi secretory pathway. They are then taken up by
multivesicular bodies (MVBs), which fuse with the plasma membrane to release the sEVs [Figure 1]. sEVs,
which are generally 30-100 nm in size, differ greatly in size from DCVs (100-200 nm).

MECHANISMS OF PROTEIN SORTING AT THE TRANS-GOLGI NETWORK TO THE RSP
Regulated secretory proteins, which include peptide hormones and neurotrophins and their precursors, as
well as granins, have a signal peptide at the N-terminus that directs them to the rough endoplasmic
reticulum (RER) cisternae after synthesis. They are then transported to the Golgi complex, where they are
sorted at the trans-Golgi network (TGN), prior to their entry to immature secretory vesicles. The hormones
and neurotrophic precursors are proteolytically processed within the immature secretory vesicles
[Figure 1]. These secretory vesicles then mature to become large (DCV, about 100-200 nm in diameter). The
DCVs, which mainly include neurotrophins, neuropeptides or peptide hormones, are stored until
stimulated to release. They release their contents slowly upon repeated stimulation or at low concentrations
of calcium [12,13] , and are then replenished. Many reviews [4,14-18] have been written about the mechanisms of
sorting and packaging of peptide hormones and neurotrophins into the vesicles of the RSP. A brief
summary of the RSP is presented in Figure 1. Here, we have highlighted examples of RSP protein sorting
mechanisms. For the correct packaging of RSP proteins to (neuro)endocrine DCVs, there should be an
elaborate process to sort RSP proteins to DCVs at the lumenal space of the TGN. The process is called