Neurotensins and Related Peptides

Definition
Neurotensin (NT) is a biologically active tridecapeptide isolated from the hypothalamus. It has been shown to induce hypotension in the rat, to stimulate contraction of guinea pig ileum and rat uterus, and to cause relaxation of rat duodenum. There is also evidence that it acts as both a peripheral and a central nervous system neurotransmitter1.

Related peptides
NT gene was isolated and sequenced and found to consist of a 10.2-kilobase segment containing 4 exons and 3 introns. The gene encodes a 170-amino acid precursor protein containing both the tridecapeptide NT and a closely related hexapeptide, neuromedin N (NN). The four amino acids at the carboxy terminal of NT and NN are identical, and amino acids 8-13 of NT are essential for biologic activity. The NT/neuromedin N (NT/NN) gene is highly conserved between species2.

Discovery
NT2 was first isolated in 1973 from bovine hypothalamus by Carraway and Leeman. In 1988, the rat NT gene was isolated and sequenced by Kislauskis et al. in 19882.

Structural Characteristics
NT is a 13-amino acid peptide (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu) and its analogue neuromedin-N (Lys-Ile-Pro-Tyr-Ile-Leu) (Minamino et al., 1984) is synthesized by a common precursor in mammalian brain (Kislauskis et al., 1988) and intestine (Dobner et al., 1987) 3,4. NT shares significant similarity in its 6 C-terminal amino acids with several other neuropeptides, including neuromedin N. This region is responsible for the biological activity, the N-terminal portion having a modulatory role5.

Mode of Action
NT is a brain and gastrointestinal peptide that fulfils many central and peripheral functions through its interaction with specific receptors. Three subtypes of neurotensin receptors have been cloned. Two of them belong to the family of G protein-coupled receptors, whereas the third one is an entirely new type of neuropeptide receptor and is identical to gp95/sortilin, a 100 kDa-protein with a single transmembrane domain4. Both central and peripheral modes of action of neurotensin imply as a first step the recognition of the peptide by a specific receptor located on the plasma membrane of the target cell. Formation of the neurotensin-receptor complex is then translated inside the cell by a change in the activity of an intracellular enzyme1.

Functions
Like many other neuropeptides, NT is a messenger of intracellular communication working as a neurotransmitter or neuromodulator in the brain and as a local hormone in the periphery. Thus, several pharmacological, morphological, and neurochemical data suggest that one of the functions of NT in the brain is to regulate dopamine neurotransmission along the nigrostriatal and mesolimbic pathways. NT is distributed throughout the central nervous system, with highest levels in the hypothalamus, amygdala and nucleus accumbens. It induces a variety of effects, including: analgesia, hypothermia and increased locomotor activity. It is also involved in regulation of dopamine pathways. On the other hand, the likely role of NT as a parahormone in the gastrointestinal tract has been well documented. In the periphery, NT is found in endocrine cells of the small intestine, where it leads to secretion and smooth muscle contraction1,6.

References
1.Vincent JP (1995). Neurotensin receptors: binding properties, transduction pathways, and structure. Cell Mol Neurobiol., 15(5):501-512.
2.Kislauskis E, Bullock B, McNeil S, Dobner PR.(1988). The rat gene encoding neurotensin and neuromedin N. Structure, tissue-specific expression, and evolution of exon sequences. J Biol Chem., 263(10):4963-4968.
3.Minamino N, Kangawa K, Matsuo H.(1984). Neuromedin N: a novel neurotensin-like peptide identified in porcine spinal cord. Biochem Biophys Res Commun., 122(2):542-549.
4.Dobner PR, Barber DL, Villa-Komaroff L, McKiernan C.( 1987). Cloning and sequence analysis of cDNA for the canine neurotensin/neuromedin N precursor. PNAS., 84(10):3516-20.
5.Binder EB, Kinkead B, Owens MJ and Nemeroff CB. (2001). Neurotensin and Dopamine Interactions. Pharmacol Rev., 53(4):453-486.
6.Vincent JP, Mazella J, Kitabgi P. (1999). Neurotensin and neurotensin receptors. Trends Pharmacol Sci., 20(7):302-309.