Three additional families encompass pheromone receptors, Dictyostelium cAMP receptors and proteins of the frizzled/smoothened receptor group. These receptors display a hepta-helical transmembrane organisation, but for most of these receptors the terminology 'G protein-coupled receptor' is controversially discussed because the relevance of G protein coupling for receptor's signal transduction was not or not convincingly demonstrated.
The 'orphan' GPCRs are cloned GPCRs that bind unknown ligands. More than 200 'orphan' GPCRs, not including the olfactory GPCRs, have been discovered so far. In most cases, the extent of sequence homology is insufficient to assign these 'orphan' receptors to a particular receptor subfamily. Once the sequence of a GPCR is known, understanding the function of the encoded protein becomes a task of paramount importance. Consequently, reverse molecular pharmacological and functional genomic strategies are being employed to identifythe activating ligands of the cloned receptors. The reverse molecular pharmacological methodology includes expression of orphan GPCRs in mammalian cells and screening these cells for a functional response to cognate or surrogate agonists present in biological extract preparations or peptide and compound libraries (Debouck and Metcalf 2000). Many new transmitter/receptor systems have been discovered recently and their physiological functions and potential relevance in human disease are currently being analysed (see Chapters 9 and 10).
GPCRs are not only encoded by eukaryotic genes but also by viral genes. To date, 18 putative GPCRs have been identified within herpes and pox viruses. Involvement of GPCRs in the pathophysiologic role of viruses has been impressively demonstrated for the Kaposi's sarcoma-associated herpes virus (KSHV) receptor and so-called UL78 gene family found in the cytomegalovirus (Oliveira and Shenk 2001). The KSHV-GPCR, closely related to chemokine and interleukin receptors, was found to agonist-independently activate the Gq/n/PLC signal transduction pathway (Arvanitakis et al. 1997).
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