Emerging roles for orphan G-protein-coupled receptors in the cardiovascular system

Despite current drug therapies, including those that target enzymes, channels and known G-protein-coupled receptors (GPCRs), cardiovascular disease remains the major cause of ill health, which suggests that other transmitter systems might be involved in this disease. In humans, ∼175 genes have been predicted to encode ‘orphan’ GPCRs, where the endogenous ligand is not yet known. As a result of intensive screening using ‘reverse pharmacology’, an increasing number of orphan receptors are being paired with their cognate ligands, many of which are peptides. The existence of some of these peptides such as urotensin-II and relaxin had been known for some time but others, including ghrelin and apelin, represent novel sequences. The pharmacological characterization of these emerging peptide–receptor systems is a tantalising area of cardiovascular research, with the prospect of identifying new therapeutic targets.