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Neurotrophin-3 Sorts to the Constitutive Secretory Pathway of
Hippocampal Neurons and Is Diverted to the Regulated Secretory Pathway
by Coexpression with Brain-Derived Neurotrophic Factor
Hooman F.
Farhadi1,
S.
Javad
Mowla1,
Kevin
Petrecca2,
Stephen J.
Morris1,
Nabil G.
Seidah3, and
Richard A.
Murphy1
1 Center for Neuronal Survival, Department of Neurology
and Neurosurgery, Montreal Neurological Institute, McGill University,
Montreal, Quebec, Canada H3A 2B4, 2 Department of
Physiology, McGill University, Montreal, Quebec, Canada H3G 1Y6, and
3 Laboratory of Biochemical Neuroendocrinology, Clinical
Research Institute of Montreal, Montreal, Quebec, Canada H2W 1R7
Hippocampal neurons release nerve growth factor (NGF) through the
constitutive secretory pathway, thus allowing the protein to be
continuously available for promoting nerve cell survival. In contrast,
hippocampal neurons use the regulated secretory pathway to process
brain-derived neurotrophic factor (BDNF), which alters synaptic
activity when released acutely from dense-core vesicles. Thus,
understanding how neurons sort and deliver neurotrophins may provide
clues to their functions in brain. In this study, we monitored the
processing and delivery of neurotrophin-3 (NT-3). Pulse-chase studies,
immunocytochemistry, and secretagogue-induced release experiments were
performed on cultured hippocampal neurons and AtT-20 cells infected
with vaccinia viruses encoding the NT-3 precursor (pro-NT-3). Results
show that most newly synthesized NT-3 is released through the
constitutive secretory pathway as a result of furin-mediated
endoproteolytic cleavage of pro-NT-3 in the trans-Golgi
network. Pro-NT-3 can also be diverted into the regulated secretory
pathway when cells are treated with  1-PDX, a selective inhibitor of
furin-like enzymes, or when pro-NT-3 expression is increased by
transient transfection methods. In cells coinfected with viruses coding
for pro-NT-3 and pro-BDNF, NT-3 is sorted into the regulated pathway,
stored in secretory granules, and released in response to extracellular
cues together with BDNF, apparently as a result of heterodimerization,
as suggested by coimmunoprecipitation data. Taken together, these data
show that sorting of the NT-3 precursor can occur in both the
constitutive and regulated secretory pathways, which is consistent with
NT-3 having both survival-promoting and synapse-altering functions.
Key words:
neurotrophin; NT-3; BDNF; constitutive pathway; regulated
secretory pathway; heterodimer
Copyright © 2000 Society for Neuroscience 0270-6474/00/20114059-10$05.00/0
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