Prolyl oligopeptidase binds to GAP-43 and functions without its peptidase activity.

Mol Cell Neurosci 2009 Jul 28;41(3):373-82. Epub 2009 Mar 28.

Psychiatry Discovery Technology Group, GlaxoSmithKline Pharmaceuticals, Harlow, Essex, UK.

Inhibitors of the enzyme prolyl oligopeptidase (PO) improve performance in rodent learning and memory tasks. PO inhibitors are also implicated in the action of drugs used to treat bipolar disorder: they reverse the effects of three mood stabilizers on the dynamic behaviour of neuronal growth cones. PO cleaves prolyl bonds in short peptides, suggesting that neuropeptides might be its brain substrates. PO is located in the cytosol, however, where it would not contact neuropeptides. Here, we show that mice with a targeted PO null-mutation have altered growth cone dynamics. The wild-type phenotype is restored by PO cDNAs encoding either native or a catalytically-dead enzyme. In addition, we show that PO binds to the growth-associated protein GAP-43, which is a key regulator of synaptic plasticity. Taken together, our results show that peptidase activity is not required for PO function in neurons and suggest that PO instead acts by binding to cytosolic proteins that control growth cone and synaptic function.

Download full-text PDF

Source
https://linkinghub.elsevier.com/retrieve/pii/S10447431090006
Publisher Site
http://dx.doi.org/10.1016/j.mcn.2009.03.003DOI Listing
July 2009

Publication Analysis

Top Keywords

growth cone
8
prolyl oligopeptidase
8
peptidase activity
8
mice targeted
4
contact neuropeptides
4
cytosol contact
4
targeted null-mutation
4
neuropeptides mice
4
altered growth
4
wild-type phenotype
4
phenotype restored
4
dynamics wild-type
4
cone dynamics
4
located cytosol
4
null-mutation altered
4
brain substrates
4
cones cleaves
4
cleaves prolyl
4
growth cones
4
neuronal growth
4

Similar Publications