Future perspectives

Sequencing of the entire genomes of many higher organisms will be completed in the next few years. This information will allow the identification of new GPCRs which are more distantly related to known receptors and will help to understand the function of human GPCRs as well. Hundreds of'orphan' GPCRs have been discovered so far. Defining the role of each GPCR and using this information to control GPCR activity therapeutically represents one of the major challenges for molecular medicine in the coming post-genomic era (see Chapters 9 and 10). Recent molecular characterization of cloned protein genes draws attention to alternative splicing and mRNA editing as a source of structural and functional diversity. Tissue-specific splicing has also been reported for several GPCRs and is likely to further increase the number of known GPCR isoforms. Undoubtedly, resolving the crystal structure of rhodopsin was a milestone in the history of GPCR research (Palczewski et al. 2000). This structural information provides a solid basis for further experimental structure/function relationship studies and for computed models of other GPCRs. Clearly, the success in crystallizing an integral membrane receptor will encourage projects to increase the resolution of the rhodopsin model and to analyze other GPCRs. Future attempts will aim at resolving the fine structure of different functional states in GPCR activation and the co-crystallization of a GPCR in complex with the G protein. These studies should eventually provide detailed structural information about the molecular architecture of the receptor/G protein interface. Identification of a growing number of receptor-binding proteins suggests alternative signalling mechanisms. Structural determinants within the C terminus and the intracellular loops provide potential interaction sites with other cellular proteins. The diversity of relevant interactions is likely to grow steadily, particularly since homologous and heterologous GPCR oligomerization has begun to emerge as a rather general phenomenon. The concept that monomeric GPCRs signal exclusively through heterotrimeric G proteins needs to be revised.

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