Neurotensin receptor-1 and-3 complex modulates the cellular signaling of neurotensin in the HT29 cell line

Background & Aims: The neuropeptide neurotensin (NT) exerts its intracellular effect by interacting with 3 different receptors. Two of these receptors (NTR1 and NTR2) belong to the G protein-coupled receptor family, whereas the third one (NTR3) is a type 1 receptor with a single transmembrane domain. We recently showed that the 2 structurally different receptors NTR1 and NTR3 were coexpressed in several human cancer cells on which NT exerts proliferative effects. Methods: Here, by an immunoprecipitation approach, we provide biochemical evidence for an endogenous heterodimerization of the G protein-coupled receptor NTR1 with the NTR3 in the human adenocarcinoma cell line HT29. Results: We show that both receptors are expressed and colocalized within the cell surface of HT29 cells where they already interact to form a heterodimer. The NTR1-NTR3 complex is then internalized on NT stimulation. Conclusions: The complex formed between these 2 structurally unrelated NT receptors modulates both the NT-induced phosphorylation of mitogen-activated protein kinases and the phosphoinositide (PI) turnover mediated by the NTR1.