PRIMARY STRUCTURE AND TISSUE DISTRIBUTION OF THE ORPHANIN FQ PRECURSOR

The heptadecapeptide orphanin FQ (OFQ) is a recently discovered neurop eptide that exhibits structural features reminiscent of the opioid pep tides and that is an endogenous ligand to a G protein-coupled receptor sequentially related to the opioid receptors. We have cloned both the human and rat cDNAs encoding the OFQ precursor proteins, to investiga te whether the sequence relationships existing between the opioid and OFQ systems are also found at the polypeptide precursor level, in part icular whether the OFQ precursor would encode several bioactive peptid es as do the opioid precursors, and to study the regional distribution of OFQ sites of synthesis. The entire precursor protein displays stru ctural homology to the opioid peptide precursors, especially preprodyn orphin and preproenkephalin. The predicted amino acid sequence of the OFQ precursor contains a putative signal peptide and one copy of the O FQ sequence flanked by pairs of basic amino acid residues. Carboxyl-te rminal to the OFQ sequence, the human and rat precursors contain a str etch of 28 amino acids that is 100% conserved and thus may encode nove l bioactive peptides. Two peptides derived from this stretch were synt hesized but were found to be unable to activate the OFQ receptor, sugg esting that if they are produced in vivo, these peptides would likely recognize receptors different from the OFQ receptor. To begin analyzin g the sites of OFQ mRNA synthesis, Northern analysis of human and rat tissues were carried out and showed that the OFQ precursor mRNA is mai nly expressed in the brain, In situ hybridization of rat brain slices demonstrated a regional distribution pattern of the OFQ precursor mRNA , which is distinct from that of the opioid peptide precursors. These data confirm that the OFQ system differs from the opioid system at the molecular level, although the OFQ and opioid precursors may have aris en from a common ancestral gene.