Neurotensin and Neuromedin N Are Differentially Processed from a Common Precursor by Prohormone Convertases in Tissues and Cell Lines

Abstract

Neurotensin (NT) is synthesized as part of a larger precursor that also contains neuromedin N (NN), a six amino acid NT-like peptide. NT and NN are located in the C-terminal region of the precursor (pro-NT/NN) where they are flanked and separated by three Lys-Arg sequences. A fourth dibasic sequence is present in the middle of the precursor. Dibasics are the consensus sites recognized and cleaved by specialized endoproteases that belong to the family of proprotein convertases (PCs). In tissues that express pro-NT/NN, the three C-terminal Lys-Arg sites are differentially processed, whereas the middle dibasic is poorly cleaved. Processing gives rise mainly to NT and NN in the brain, NT and a large peptide with a C-terminal NN moiety (large NN) in the gut, and NT, large NN, and a large peptide with a C-terminal NT moiety (large NT) in the adrenals. Recent evidence indicates that PC1, PC2, and PC5-A are the prohormone convertases responsible for the processing patterns observed in the gut, brain, and adrenals, respectively. As NT, NN, large NT, and large NN are all endowed with biological activity, the evidence reviewed here supports the idea that posttranslational processing of pro-NT/NN in tissues may generate biological diversity of pathophysiological relevance.

Emerging role of neurotensin in regulation of the cardiovascular system

“…Activation of the NTS 1 receptor results in stimulation of the phosphatidylinositol hydrolysis with a subsequent mobilization of Ca 2 þ release from intracellular stores. Apart of NT, this receptor subtype could be activated by neuromedin N, an endogenous hexapeptide produced along with NT during proteolytic processing of the common precursor protein molecule (proneurotensin 1-117) Kitabgi, 2010). This is accounted for by similarity of the amino acid sequence of neuromedin N (Lys-Ile-Pro-Tyr-Ile-Leu) and the C-terminal fragment of NT (NT 8-13 : Arg-Arg-Pro-Tyr-Ile-Leu) that is responsible for NTS 1 receptor activation.…”

Improved sensitivity of the nano ultra-high performance liquid chromatography-tandem mass spectrometric analysis of low-concentrated neuropeptides by reducing aspecific adsorption and optimizing the injection solvent

“…kassinin-like peptides (neuromedin K and L), bombesin-like peptides (neuromedin B and C), a neurotensin-like peptide (neuromedin N) and the group of neuromedin U and S [4,5]. Besides their well-known effects on peripheral functions [6][7][8][9], there is also increased interest for unveiling the potential role of neuromedin peptides in neurological disorders. To study brain neuromedin levels and dynamics as a function of time, microdialysis is used as in vivo sampling tool [10].…”

Cell-Specific Precursor Processing

“…The neurotensin (NT) gene is expressed predominantly in the hypothalamus and the neurons of some other brain areas and nuclei, in the adrenal glands, and in endocrine, small intestinal N-cells. The whole biosynthesis and processing story of proneurotensin is detailed later by Kitabgi (2009) in this volume (see also Kitabgi 2006). In the present context it suffices to state that proneurotensin contains two bioactive sequences in its C-terminal part: the tridecapeptide NT and the hexapeptide neuromedin N (NN).…”