期刊
JOURNAL OF NEUROCHEMISTRY
卷 106, 期 1, 页码 384-391出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1471-4159.2008.05408.x
关键词
cathepsin L; neuropeptide; NPY; prohormone processing; protease; secretory vesicles
资金
- NHLBI NIH HHS [P01 HL058120-089004, P01 HL058120-01A19004, P01 HL058120, P01 HL058120-029004, P01 HL058120-06A19004, P01 HL058120-030003, P01 HL058120-099004, P01 HL058120-039004, P01 HL058120-079004, P01 HL058120-090003, P01 HL058120-049004, P01 HL058120-01A10003, P01 HL058120-020003, P01 HL058120-080003, P01 HL058120-059004, P01 HL058120-050003, P01 HL058120-04S19004, P01 HL058120-070003, P01 HL058120-04S10003, P01 HL058120-06A10003, P01 HL058120-040003] Funding Source: Medline
Neuropeptide Y (NPY) functions as a peptide neurotransmitter and as a neuroendocrine hormone. The active NPY peptide is generated in secretory vesicles by proteolytic processing of proNPY. Novel findings from this study show that cathepsin L participates as a key proteolytic enzyme for NPY production in secretory vesicles. Notably, NPY levels in cathepsin L knockout (KO) mice were substantially reduced in brain and adrenal medulla by 80% and 90%, respectively. Participation of cathepsin L in producing NPY predicts their colocalization in secretory vesicles, a primary site of NPY production. Indeed, cathepsin L was colocalized with NPY in brain cortical neurons and in chromaffin cells of adrenal medulla, demonstrated by immunofluorescence confocal microscopy. Immunoelectron microscopy confirmed the localization of cathepsin L with NPY in regulated secretory vesicles of chromaffin cells. Functional studies showed that coexpression of proNPY with cathepsin L in neuroendocrine PC12 cells resulted in increased production of NPY. Furthermore, in vitro processing indicated cathepsin L processing of proNPY at paired basic residues. These findings demonstrate a role for cathepsin L in the production of NPY from its proNPY precursor. These studies illustrate the novel biological role of cathepsin L in the production of NPY, a peptide neurotransmitter, and neuroendocrine hormone.
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