Clearly, scientists now have access to high-throughput technologies to identify ligands for orphan receptors. A number of these are able to produce a functional readout, directed through a single pathway, allowing ligands to be found without knowledge of the receptors endogenous coupling mechanism. Based on the diversity of ligands which have been paired, it is likely that various assay formats and a much larger array of ligands will be needed to pair the remaining orphans. But, this may still not yield the complete picture of receptor : ligand pairs as we need to bear in mind the lessons learned from the calcitonin receptor-like receptor (CRLR) which requires receptor activity modifying proteins (RAMPs) to express the full array of pharmacological phenotypes (McLatchie et al. 1998, see chapter 7). This highlights the importance of additional variables in assay design to characterize orphan GPCRs and discover new ligands. Although it is unclear to what extent GPCRs employ the RAMP proteins but recently another example has been reported, functional amylin receptors are dependent on RAMP1 or RAMP3 coexpression (Christopoulos et al. 1999). Another variable is the recent observations that GPCRs oligomerise. Both homo- and hetero-examples have been described and the importance clearly demonstrated in the discovery of the GABAb receptor (Jones et al. 1998; White et al. 1998; Kaupman et al. 1998, see chapter 28). However, the importance, in the broadest context, of these observations pharmacologically is the subject of considerable debate (Bouvier 2001). Clearly, if oligomerization is involved in trafficking or receptor function this could have an effect on the ability to identify ligands for orphan receptors. However, the best measure of success for any initiative to identify ligands for orphan receptors will be the number of new, validated targets, and ultimately those that lead to novel therapies in the clinic. Time will be the judge and jury.
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