NEUROTENSIN IS AN ANTAGONIST OF THE HUMAN NEUROTENSIN NT2 RECEPTOR EXPRESSED IN CHINESE-HAMSTER OVARY CELLS

The human levocabastine-sensitive neurotensin NT2 receptor was cloned from a cortex cDNA Library and stably expressed in Chinese hamster ova ry (CHO) cells in order to study its binding and signalling characteri stics. The receptor binds neurotensin as well as several other ligands already described for neurotensin NT1 receptor. It also binds levocab astine, a histamine H-1 receptor antagonist that is not recognised by neurotensin NT1 receptor. Neurotensin binding to recombinant neurotens in NT2 receptor expressed in CHO cells does not elicit a biological re sponse as determined by second messenger measurements. Levocabastine, and the peptides neuromedin N and xenin were also ineffective on neuro tensin NT2 receptor activation. Experiments with the neurotensin NT1 r eceptor antagonists SR48692 and SR142948A, resulted in the unanticipat ed discovery that both molecules are potent agonists on neurotensin NT 2 receptor. Both compounds, following binding to neurotensin NT2 recep tor, enhance inositol phosphates (IP) formation with a subsequent [Ca2 +](i) mobilisation; induce arachidonic acid release; and stimulate mit ogen-activated protein kinase (MAPK) activity. Interestingly, these ac tivities are antagonised by neurotensin and levocabastine in a concent ration-dependent manner. These activities suggest that the human neuro tensin NT2 receptor may be of physiological importance and that a natu ral agonist for the receptor may exist. (C) 1998 Elsevier Science B.V. All rights reserved.