Protein scaffoldings and modular signaling through seven transmembrane domains-receptors:: beyond the G proteins

G protein coupled receptors (GPCR) represent one of the largest families of proteins encoded by the human genome. They mediate cellular communications important in many fundamental physiological processes. Until recently, GPCR function was thought to be mediated almost exclusively via the obligatory activation of hetero-trimeric G proteins. The development of molecular biological approaches and methods to assess protein-protein interactions have now markedly broadened this view. It is now apparent that proteins such as receptor kinases and arrestins, which quench the signaling function of GPCR, are themselves capable of functioning either as effecters or adaptors that initiate and regulate non-conventional signaling pathways or cell biological processes involved in receptor function. Similarly, the direct interaction of GPCR either through specific sequence motifs, or conformations with small molecular weight G proteins, enzymes, ion channels or scaffolding proteins indicates a larger than expected diversity in the physiological processes affected by this receptor family. Finally, the realization that homo- and heterodimerization of GPCR as well as interactions with escort proteins can influence their processing, trafficking, ligand binding and signaling specificity points to levels of complexity and diversity that were unsuspected. Unraveling the molecular principles of these interactions and their physiological relevance provides new challenges that will undoubtedly reveal novel targets for the development of therapeutic interventions.