Unravelling multiple ligand-activation binding sites using RASSL receptors

The principle of receptors activated solely by synthetic ligands (RASSLs) as discovered for chimeric opioid peptide receptors has been extended to point-mutated 5-HT4 receptors and alpha(2A)-adrenoceptors. On binding to these RASSLs, which are insensitive to their native ligands, synthetic ligands exhibit either similar, lower or higher agonist efficacy than they exhibit following binding to wild-type receptors. Furthermore, several antagonists demonstrate potent agonist responses following binding to RASSLs. The recent development of new RASSLs raises the potential for in vivo stimulation of multiple signalling pathways with ligands that have no agonist potential at wild-type receptors, which could improve our understanding of receptor signalling.