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The Novel Role of Cathepsin L for Neuropeptide Production Illustrated by Research Strategies in Chemical Biology with Protease Gene Knockout and Expression

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Proprotein Convertases

Part of the book series: Methods in Molecular Biology ((MIMB,volume 768))

Abstract

Neuropeptides are essential for cell–cell communication in the nervous and endocrine systems. Production of active neuropeptides requires proteolytic processing of proneuropeptide precursors in secretory vesicles that produce, store, and release neuropeptides that regulate physiological functions. This review describes research strategies utilizing chemical biology combined with protease gene knockout and expression to demonstrate the key role of cathepsin L for production of neuropeptides in secretory vesicles. Cathepsin L was discovered using activity-based probes and mass spectrometry to identify proenkephalin cleaving activity as cathepsin L. Significantly, in vivo protease gene knockout and expression approaches illustrate the key role of cathepsin L for neuropeptide production. Notably, cathepsin L is colocalized with neuropeptide secretory vesicles, the major site of proteolytic processing of proneuropeptides to generate active neuropeptides. Cathepsin L participates in producing opioid neuropeptides consisting of enkephalin, β-endorphin, and dynorphin, as well as in generating the POMC-derived peptide hormones ACTH and α-MSH. In addition, NPY, CCK, and catestatin neuropeptides utilize cathepsin L for their biosynthesis. The role of cathepsin L for neuropeptide production indicates its unique biological role in secretory vesicles, which contrasts with its role in lysosomes for protein degradation. Interesting evaluations of protease gene knockout studies in mice that lack cathepsin L compared to the PC1/3 and PC2 (PC, prohormone convertase) indicate the significant role of cathepsin L in neuropeptide production. Thus, dual cathepsin L and prohormone convertase protease pathways participate in neuropeptide production. These recent new findings indicate cathepsin L as a novel ‘proprotein convertase’ for production of neuropeptides that mediate cell–cell communication in health and disease.

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Acknowledgments

The authors appreciate support of this research by grants to V. Hook from the National Institutes of Health. The authors also appreciate scientific advice by Dr. Shin-Rong Hwang and technical assistance by Mr. Thomas Toneff at the Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA.

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Authors and Affiliations

  1. Department of Neuroscience, Pharmacology, and Medicine, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA, 93093, USA

    Lydiane Funkelstein & Vivian Hook

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  1. Lydiane Funkelstein
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  2. Vivian Hook
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Correspondence to Vivian Hook .

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Editors and Affiliations

  1. Chronic Disease Program, Ottawa Hospital Research Institute, Parkdale Avenue 725, Ottawa, K1Y 4E9, Ontario, Canada

    Majambu Mbikay

  2. (ICRM), Lab. Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Avenue des Pins Ouest 110, Montreal, H2W 1R7, Québec, Canada

    Nabil G. Seidah

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Funkelstein, L., Hook, V. (2011). The Novel Role of Cathepsin L for Neuropeptide Production Illustrated by Research Strategies in Chemical Biology with Protease Gene Knockout and Expression. In: Mbikay, M., Seidah, N. (eds) Proprotein Convertases. Methods in Molecular Biology, vol 768. Humana Press. https://doi.org/10.1007/978-1-61779-204-5_5

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  • DOI: https://doi.org/10.1007/978-1-61779-204-5_5

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  • Publisher Name: Humana Press

  • Print ISBN: 978-1-61779-203-8

  • Online ISBN: 978-1-61779-204-5

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