Subtypes of the somatostatin receptor assemble as functional homo- and heterodimers

The existence of receptor dimers has been proposed for several G protein-co upled receptors. However, the question of whether G protein-coupled recepto r dimers are necessary for activating or modulating normal receptor functio n is unclear. We address this question with somatostatin receptors (SSTRs) of which there are five distinct subtypes. By using transfected mutant and wild type receptors, as well as endogenous receptors, we provide pharmacolo gical, biochemical, and physical evidence, based on fluorescence resonance energy transfer analysis, that activation by ligand induces SSTR dimerizati on, both homo- and heterodimerization with other members of the SSTR family , and that dimerization alters the functional properties of the receptor su ch as ligand binding affinity and agonist-induced receptor internalization and up-regulation. Double label confocal fluorescence microscopy showed tha t when SSTR1 and SSTR5 subtypes were coexpressed in Chinese hamster ovary-K 1 cells and treated with agonist they underwent internalisation and were co localized in cytoplasmic vesicles. SSTR5 formed heterodimers with SSTR1 but not with SSTR4 suggesting that heterodimerization is a specific process th at is restricted to some but not all receptor subtype combinations. Direct protein interaction between different members of the SSTR subfamily defines a new level of molecular cross-talk between subtypes of the SSTR and possi bly related receptor families.