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Page 569 Loh et al. Extracell Vesicles Circ Nucleic Acids 2023;4:568-87 https://dx.doi.org/10.20517/evcna.2023.34

pathways for the release of hormones and neurotrophic factors from the cell may have some physiological
significance in intercellular communication.

Keywords: Hormone trafficking, trophic factor, neurons, endocrine cells, extracellular vesicles, sEV, exosomes

INTRODUCTION
Throughout evolution, from unicellular organisms to multicellular life forms, cells communicate via the
secretion of signaling molecules packaged in vesicles which are organelles bounded by a lipid bilayer
membrane . The types of secreted vesicles and content vary with the type of cell and organism. Upon
[1]
[2-6]
release, the contents of the vesicles perform various physiological functions . Early studies towards
understanding the secretory pathway in various cells were descriptive and morphological. In 1974, George
Palade won the Nobel Prize for discovering, based on electron microscopic studies, that newly synthesized
secretory proteins are transported vectorially from the endoplasmic reticulum to the Golgi apparatus and
into secretory vesicles for release. Subsequently, the pioneering work of Randy Schekman exploiting yeast
genetics transformed the secretion field into one that was molecular and mechanistic. Schekman, together
with James Rothman and Thomas Sudhof received the Nobel Prize in Physiology or Medicine in 2013 for
discovering the molecular mechanisms regulating intracellular vesicle trafficking along the secretory
pathway (for review, see ). This chapter is for a Special Issue dedicated to honoring Randy Schekman.
[7]
Although his discoveries stemmed from using yeast genetics, the proteins involved in membrane trafficking
mechanisms are highly conserved in mammalian cells. Schekman’s findings revolutionized the secretion
field from hormone secretion to cholesterol homeostasis and neurotransmitter release. Over the last decade,
his work has inspired research in the field of membrane trafficking and vesicle biogenesis in the regulated
and constitutive secretory pathways and, more recently, extracellular vesicle (EV) biogenesis, secretion and
function in different cell types. This Special Issue will begin with our chapter, recapitulating some of the
historical perspective and recent updates of the molecular mechanisms involved in the biogenesis, sorting,
and packaging of regulated secretory pathway (RSP) proteins into classical secretory vesicles, and their
intracellular trafficking and secretion in neuroendocrine cells. Each of the steps for the assembly of the RSP
is highly orchestrated to ensure proper packaging of hormone and trophic factor precursors and proteolytic
enzymes into secretory vesicles for processing to mature proteins/peptides necessary for intercellular
communication and higher physiological function. Dysregulation of the RSP in (neuro)endocrine cells
leads to various diseases. For example, improper sorting of proinsulin for processing to insulin results in
type 2 diabetes . Studies have implicated dysfunction of synaptic vesicle transport in the presynaptic
[8]
terminals of dopaminergic neurons at the substantial nigra in Parkinson’s Disease , and in Prader-Willi
[9]
Syndrome, a decrease of secretory vesicle and neuropeptide production was found, leading to impaired
hypothalamic neuroendocrine function . Next, we highlight several sEV-related papers showing that some
[10]
of these RSP proteins, including peptide hormones and neurotrophic factors, are also secreted as cargo in
sEVs. We discuss the possible physiological significance of the dual release of these RSP proteins via
classical secretory vesicles versus sEVs. Since sEVs are taken up by recipient cells, we hypothesize that these
RSP proteins may have different biological functions intracellularly as opposed to their receptor-mediated
signaling action extracellularly.

SECRETORY PATHWAYS IN (NEURO) ENDOCRINE CELLS
In the classical RSP, endocrine and neuroendocrine cells package their hormones and trophic factors into
dense core vesicles (DCVs) and release their content upon stimulation in a regulated manner, while other
[11]
secretory proteins are released constitutively without stimulation [constitutive secretory pathway (CSP)]
[Figure 1].