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