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The Journal of Neuroscience, August 15, 2001, 21(16):5864-5870

Altered Processing of Pro-Orphanin FQ/Nociceptin and Pro-Opiomelanocortin-Derived Peptides in the Brains of Mice Expressing Defective Prohormone Convertase 2

Richard G. Allen², Bonnie Peng¹, Michael J. Pellegrino², Emilie D. Miller³, David K. Grandy⁴, James R. Lundblad⁵, Carrie L. Washburn², and John E. Pintar¹

¹ Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, and ² Center for Research on Occupational and Environmental Toxicology, ³ Neuroscience Graduate Program, and Departments of ⁴ Physiology and Pharmacology and ⁵ Molecular Medicine, Oregon Health Sciences University, Portland, Oregon 97201

The bioactivity of neuropeptides can be regulated by a variety of post-translational modifications, including proteolytic processing. Here, gene-targeted mice producing defective prohormone convertase 2 (PC2) were used to examine the post-translational processing of two neuroendocrine prohormones, pro-opiomelanocortin (POMC) and pro-orphanin FQ (pOFQ)/nociceptin (N), in the brain. Reversed-phase HPLC and gel-exclusion chromatography were combined with specific radioimmunoassays to analyze the processing patterns of these two prohormones in the hypothalamus and the amygdala. In the case of POMC, the lack of PC2 activity completely prevented carboxy-shortening of -endorphins and greatly diminished conversion of -lipotropin to -lipotropin and -endorphin. Although conversion of -lipotropin to -endorphin decreased, the lack of PC2 activity caused an increase in -lipotropin and -endorphin levels in the mutant animals, but no increases in POMC or biosynthetic intermediates were seen. The extent of OFQ/N production was significantly lower in PC2-deficient mice and there was an accumulation of relatively large amounts of pOFQ/N and biosynthetic intermediates. These results demonstrate that PC2 is directly involved in the biogenesis of two brain neuropeptides in vivo and suggest that the specific prohormone and cellular context influences neuropeptide processing by PCs.

Key words: neuropeptide; proteolytic processing; pro-orphanin FQ/nociceptin; POMC; PC2; gene-targeting

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21165864-07$05.00/0

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