Sturgeon orphanin, a molecular "fossil" that bridges the gap between the opioids and orphanin FQ/nociceptin

The elucidation of the cDNA sequence for sturgeon proorphanin provides a un ique window for interpreting the evolutionary history of the opioid/orphani n gene family. The molecular "fossil" status of this precursor can be seen in several ancestral sequence characteristics that point to its origin as a duplication of either a prodynorphin- or proenkephalin-like gene. The stur geon proorphanin cDNA encodes a precursor protein of 194 residues, and the orphanin heptadecapeptide itself binds not only the opioid receptor-like 1 (ORL1) receptor but also the classical (mu, kappa, and delta) opioid recept ors with near equal affinity. Allowing for this broad receptor specificity are several amino acid substitutions at key positions in the heptadecapepti de sequence, relative to its mammalian orthologs, that have been linked by amino acid scans and site directed mutagenic studies to the exclusion of ma mmalian orphanin FQ/nociceptin from classic opioid ligands (i.e. F1Y and L1 4W). The unique receptor binding profile of sturgeon orphanin not only prov ides insight into the evolutionary history of the opioid and opioid-related peptides but also provides an ideal context in which to investigate the un der lying mechanisms by which novel and often divergent physiological funct ions arise in receptor-ligand systems.