期刊
JOURNAL OF NEUROCHEMISTRY
卷 83, 期 6, 页码 1329-1337出版社
WILEY
DOI: 10.1046/j.1471-4159.2002.01244.x
关键词
7B2; cholecystokinin; neuropeptides; post-translational processing; procholecystokinin; prohormone convertase
资金
- NIDA NIH HHS [DA 05084] Funding Source: Medline
- NIDDK NIH HHS [R01 DK049703, DK 49703] Funding Source: Medline
In addition to its role as a gut hormone, cholecystokinin (CCK) is a widespread and potent neurotransmitter. Its biosynthesis requires endoproteolytic cleavage of proCCK at several mono- and dibasic sites by subtilisin-like prohormone convertases (PCs). Of these, PC1 and PC2 are specific for neuroendocrine cells. We have now examined the role of PC2 and its binding protein, 7B2, in the neuronal processing of proCCK by measurement of precursor, processing-intermediates and bioactive end-products in brain extracts from PC2- and 7B2-null mice and from corresponding controls. PC2-null mice displayed a nine-fold increase of cerebral proCCK concentrations, and a two-fold increase in the concentrations of the processing-intermediate, glycine-extended CCK, whereas the concentrations of transmitter-active (i.e. alpha-amidated and O -sulfated) CCK peptides were reduced (61%). Chromatography showed that O -sulfated CCK-8 still is the predominant transmitter-active CCK in PC2-null brains, but that the fraction of intermediate-sized CCK-peptides (CCK-58, -33 and -22) was eight-fold increased. 7B2-null brains displayed a similar pattern but with less pronounced precursor accumulation. In contrast with the cerebral changes, PC2 deficiency was without effect on proCCK synthesis and processing in intestinal endocrine cells, whereas 7B2 deficiency halved the concentration of bioactive CCK in the intestine. The results show that PC2 plays a major neuron-specific role in the processing of proCCK.
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