G-protein-coupled receptors (GPCR) are now, regarded as being able to acquire heterodimer conformations affecting their pharmacology. signaling and trafficking in co-immunoprecipitation Studies using differentially epitope-tagged receptors. we herein provide direct evidence for heterodimerization of human neurotensin type 1 receptor (hNTR1) and type 2 receptor (hNTR2) Using chimeric constructs. we also identified the hNTR2 transmembrane 2 (TM2) to TM4 region as crucial for the formation of the dimerization interface. At the functional level, we demonstrated that the co-expression of hNTR2 suppressed hNTR1-mediated adenylate cyclase/cAMP and phospholipase C activation Finally, confocal microscopy revealed that whereas tagged hNTR1 expressed alone were localized to the plasma membrane. co-expression of hNTR2 caused the retention of hNTR1 in sub-cellular compartments, indicating that heterodimerization with hNTR2 interferes with the proper recruitment of hNTR1 to the plasma membrane Overall. this study proposes a novel function of NTR2 in the regulation of NTR1 activity (C) 2009 Elsevier Inc All rights reserved