History and biological significance of GPCR heteromerization in the neuroendocrine system.

G protein-coupled receptors (GPCRs) constitute a large family of seven transmembrane proteins that regulate major cellular functions. The important role of GPCRs in the neuroendocrine system is outlined by the great interest of pharmaceutical companies in developing new drugs targeting these receptors. GPCRs exist as monomers, but can also be organized in oligomeric structures composed of either homo- or heteromers. GPCR heteromerization may play an important role in modulating and fine-tuning GPCR function and signaling. The literature reports many examples of GPCR heteromers in vitro raising the question of the physiological relevance of these complexes in tissues. Considerable efforts are currently being directed towards conclusive evidence for the existence of GPCRs heteromers in vivo, a crucial step for the validation of the concept of GPCR heteromerization and future drug development. The present review will give a brief history of GPCR oligomerization and emphasize the importance and physiological relevance of GPCR heteromerization by discussing key examples of GPCR couples.