The diversity of receptor groups within the GPCR superfamily is the result of a long evolutionary process. It has been suggested that serotonin (5-HT) receptors have existed for more than 750 million years (Peroutka and Howell 1994). The tendency towards protein diversification depends upon gene duplications and the continuous accumulation of mutations. The maintenance of vital functions in organisms, however, strictly requires enough structural conservation to ensure the functionality of the corresponding proteins. Despite the remarkable structural variety of natural GPCR agonists, hydropathy analysis, biochemical, and immunological data suggest that all GPCRs share a common molecular architecture consisting of seven transmembrane domains (TMDs) connected by three extra- and three intracellular loops. Interestingly, this global architecture is maintained in all GPCRs discovered so far, despite a rather low amino acid sequence homology.
Molecular cloning studies and genome data analysis have revealed at least 1200 members of the GPCR superfamily in the human genome. About 40-60% out of all human GPCRs have orthologs in other species including more distantly related organisms such as Caenorhabditis elegans and Drosophila melanogaster. The GPCR superfamily comprises at least three families which share little sequence homology among each other (Fig. 1.1). To date, about 190 GPCRs have been assigned to an agonist or potential ligands. More than 900 are olfactory GPCRs. The remaining GPCRs are so called 'orphan' receptors or pseudogenes in man.
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