Activity-Dependent Release of Precursor Nerve Growth Factor, Conversion to Mature Nerve Growth Factor, and Its Degradation by a Protease Cascade

In this report, we provide direct demonstration that the neurotrophin nerve growth factor (NGF) is released in the extracellular space in an activity-dependent manner in its precursor form (proNGF) and that it is in this compartment that its maturation and degradation takes place because of the coor...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2006-04, Vol.103 (17), p.6735-6740
Main Authors: Bruno, Martin A., Cuello, A. Claudio
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Calcium
Central nervous system
Cerebral cortex
Cerebral Cortex - metabolism
Enzyme Activation
Enzymes
Extracellular space
Extracellular Space - metabolism
Humans
Matrix Metalloproteinase 9 - metabolism
Models, Neurological
Nerve Growth Factor - metabolism
Nerve tissue
Nerves
Nervous system
Neurons
Neuroscience
Neurosciences
Peptide Hydrolases - metabolism
Protein Precursors - metabolism
Rats
Rats, Inbred F344
Receptors
Secretion
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:In this report, we provide direct demonstration that the neurotrophin nerve growth factor (NGF) is released in the extracellular space in an activity-dependent manner in its precursor form (proNGF) and that it is in this compartment that its maturation and degradation takes place because of the coordinated release and the action of proenzymes and enzyme regulators. This converting protease cascade and its endogenous regulators (including tissue plasminogen activator, plasminogen, neuroserpin, precursor matrix metalloproteinase 9, and tissue inhibitor metalloproteinase 1) are colocalized in neurons of the cerebral cortex and released upon neuronal stimulation. We also provide evidence that this mechanism operates in in vivo conditions, as the CNS application of inhibitors of converting and degrading enzymes lead to dramatic alterations in the tissue levels of either precursor NGF or mature NGF. Pathological alterations of this cascade in the CNS might cause or contribute to a lack of proper neuronal trophic support in conditions such as cerebral ischemia, seizure and Alzheimer's disease or, conversely, to excessive local production of neurotrophins as reported in inflammatory arthritis pain.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0510645103