Inverse agonism at neurotensin receptors NTS1 and NTS2

Abstract

Neurotensin (NT) is a peptide expressed in the brain and small intestines. Its central effects include analgesia, inhibition of food intake, modulation of central dopaminergic systems, and modulation of pituitary hormones secretion. In the gut, neurotensin is released upon food ingestion to regulate digestive functions. In addition, the peptide acts as a trophic factor on human colon, pancreatic, prostate, and lung cancer cell lines. Thus, neurotensin receptors represent interesting targets for the treatment of pain, obesity, schizophrenia, and cancer. Two neurotensin receptors, NTS1 and NTS2, that belong to the family of G protein-coupled receptors have been identified. A nonpeptide antagonist with selectivity for the NTS1, SR 48692, has been characterized. Recent mutagenesis and modeling studies allowed us to map agonist and antagonist binding sites in the NTS1 and to identify extracellular and transmembrane (TM) residues involved in receptor activation. In particular, we identified a transmembrane residue whose mutation confers constitutive activity to the NTS1 and reveals inverse agonist properties of SR 48692. Quite recently, we demonstrated that the human NTS2 is constitutively active and we characterized agonist, inverse agonist, and neutral antagonist ligands at this receptor. These results and their implications are the focus of the present paper.