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

• Published in: Molecular and cellular neuroscience 2010, Vol.43 (1), p.98-107
• Main Authors: Minokadeh, Ardalan, Funkelstein, Lydiane, Toneff, Thomas, Hwang, Shin-Rong, Beinfeld, Margery, Reinheckel, Thomas, Peters, Christoph, Zadina, James, Hook, Vivian
• Format: Article
• Language: English
• Subjects: Animals; Cathepsin L - genetics; Cathepsin L - metabolism; Cerebral Cortex - cytology; Cerebral Cortex - metabolism; Dynorphins - genetics; Dynorphins - metabolism; Gene Knockout Techniques; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons - cytology; Neurons - metabolism; PC12 Cells; Proprotein Convertase 1 - genetics; Proprotein Convertase 1 - metabolism; Proprotein Convertase 2 - genetics; Proprotein Convertase 2 - metabolism; Protein Precursors - genetics; Protein Precursors - metabolism; Rats
• ISSN: 1044-7431; 1095-9327; 1095-9327
• DOI: 10.1016/j.mcn.2009.10.001

Dynorphin opioid neuropeptides mediate neurotransmission for analgesia and behavioral functions. Dynorphin A, dynorphin B, and α-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 α-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 α-neoendorphin. Overall, these results demonstrate a prominent role for cathepsin L, jointly with PC1/3 and PC2, for production of dynorphins in brain.