Article

Cathepsin L participates in dynorphin production in brain cortex, illustrated by protease gene knockout and expression.

Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
Molecular and Cellular Neuroscience (impact factor: 3.66). 10/2009; 43(1):98-107. DOI:10.1016/j.mcn.2009.10.001
Source: PubMed

ABSTRACT Dynorphin opioid neuropeptides mediate neurotransmission for analgesia and behavioral functions. Dynorphin A, dynorphin B, and alpha-neoendorphin are generated from prodynorphin by proteolytic processing. This study demonstrates the significant role of the cysteine protease cathepsin L for producing dynorphins. Cathepsin L knockout mouse brains showed extensive decreases in dynorphin A, dynorphin B, and alpha-neoendorphin that were reduced by 75%, 83%, and 90%, respectively, compared to controls. Moreover, cathepsin L in brain cortical neurons was colocalized with dynorphins in secretory vesicles, the primary site of neuropeptide production. Cellular coexpression of cathepsin L with prodynorphin in PC12 cells resulted in increased production of dynorphins A and B. Comparative studies of PC1/3 and PC2 convertases showed that PC1/3 knockout mouse brains had a modest decrease in dynorphin A, and PC2 knockout mice showed a minor decrease in alpha-neoendorphin. Overall, these results demonstrate a prominent role for cathepsin L, jointly with PC1/3 and PC2, for production of dynorphins in brain.

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Keywords

alpha-neoendorphin
 
B. Comparative studies
 
behavioral functions
 
brain cortical neurons
 
cathepsin L
 
Cathepsin L knockout mouse brains
 
cysteine protease cathepsin L
 
dynorphin B
 
Dynorphin opioid neuropeptides
 
dynorphins
 
extensive decreases
 
minor decrease
 
modest decrease
 
PC1/3 knockout mouse brains
 
PC12 cells
 
PC2 convertases
 
PC2 knockout mice
 
proteolytic processing
 
secretory vesicles