Abstract
Neurotensin is a 13-amino acid peptide (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu) originally isolated from hypothalami (Carraway and Leeman, 1973) and later from intestines (Kitabgi et al., 1976) of bovine. The peptide is present throughout the animal kingdom, suggesting its participation to important processes basic to animal life (Carraway et al., 1982). Neurotensin and its analogue neuromedin-N (Lys-Ile-Pro-Tyr-Ile-Leu) (Minamino et al., 1984) are synthesized by a common precursor in mammalian brain (Kislauskis et al., 1988) and intestine (Dobner et al., 1987). The central and peripheral distribution and effects of neurotensin have been extensively studied. In the brain, neurotensin is exclusively found in nerve cells, fibers, and terminals (Uhl et al., 1979), whereas the majority of peripheral neurotensin is found in the endocrine N-cells located in the intestinal mucosa (Orci et al., 1976; Helmstaedter et al., 1977). Central or peripheral injections of neurotensin produce completely different pharmacological effects (Table I) indicating that the peptide does not cross the blood-brain barrier. Many of the effects of centrally administered neurotensin are similar to those of neuroleptics or can be antagonized by simultaneous administration of TRH (Table I). The recently discovered nonpeptide antagonist SR 48692 (Gully et al., 1993) can inhibit several of the central and peripheral effects of neurotensin (Table I). Like many other neuropeptides, neurotensin is a messenger of intracellular communication working as a neurotransmitter or neuromodulator in the brain (Nemeroff et al., 1982) and as a local hormone in the periphery (Hirsch Fernstrom et al., 1980). Thus, several pharmacological, morphological, and neurochemical data suggest that one of the functions of neurotensin in the brain is to regulate dopamine neurotransmission along the nigrostriatal and mesolimbic pathways (Quirion, 1983; Kitabgi, 1989). On the other hand, the likely role of neurotensin as a parahormone in the gastrointestinal tract has been well documented (Rosell and Rökaeus, 1981; Kitabgi, 1982). 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 enzyme. This paper describes the binding and structural properties of neurotensin receptors as well as the signal transduction pathways that are activated by the peptide in various target tissues and cells.