title: Cathepsin L participates in dynorphin production in brain cortex, illustrated by protease gene knockout and expression.
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.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Ardalan
authors.initials: A
authors.lastname: Minokadeh
authors.forename: Lydiane
authors.initials: L
authors.lastname: Funkelstein
authors.forename: Thomas
authors.initials: T
authors.lastname: Toneff
authors.forename: Shin-Rong
authors.initials: SR
authors.lastname: Hwang
authors.forename: Margery
authors.initials: M
authors.lastname: Beinfeld
authors.forename: Thomas
authors.initials: T
authors.lastname: Reinheckel
authors.forename: Christoph
authors.initials: C
authors.lastname: Peters
authors.forename: James
authors.initials: J
authors.lastname: Zadina
authors.forename: Vivian
authors.initials: V
authors.lastname: Hook
mesh_terms: D000818:Animals; D056668:Cathepsin L / Q000235:genetics / Q000378:metabolism*; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D004399:Dynorphins / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D016716:PC12 Cells; D045664:Proprotein Convertase 1 / Q000235:genetics* / Q000378:metabolism; D045706:Proprotein Convertase 2 / Q000235:genetics* / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D051381:Rats
chemical_list: D011498:Protein Precursors; D004399:Dynorphins; D045664:Proprotein Convertase 1; D045706:Proprotein Convertase 2; D056668:Cathepsin L