Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor

• DOI: 10.1038/377532a0
• Publication Date: 2003-06-12T23:57:39Z
• Authors: Jean-Claude Meunier; Catherine Mollereau; Lawrence Toll; Charles Suaudeau; Christiane Moisand; Paul Alvinerie; Jean-Luc Butour; Jean-Claude Guill...; Pascual Ferrara; Bernard Monsarrat; Honoré Mazarguil; Gilbert Vassart; Marc Parmentier; Jean Costentin
• Keywords: 0301 basic medicine; DNA, Complementary; Opioid Peptides -- physiology; Molecular Sequence Data; Antisense -- pharmacology; CHO Cells; Opioid Peptides -- isolation & purification; Dynorphins; DNA, Antisense; Nociceptin Receptor; Opioid Peptides -- chemistry; 03 medical and health sciences; Complementary; Cricetinae; Receptors; Animals; Humans; Amino Acid Sequence; Base Sequence; DNA; Sciences bio-médicales et agricoles; Rats; 3. Good health; Opioid -- agonists; Opioid Peptides; Receptors, Opioid; Dynorphins -- chemistry

The ORL1 receptor, an orphan receptor whose human and murine complementary DNAs have recently been characterized, structurally resembles opioid receptors and is negatively coupled with adenylate cyclase. ORL1 transcripts are particularly abundant in the central nervous system. Here we report the isolation, on the basis of its ability to inhibit the cyclase in a stable recombinant CHO(ORL1+) cell line, of a neuropeptide that resembles dynorphin A9 and whose amino acid sequence is Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln. The rat-brain cDNA encodes the peptide flanked by Lys-Arg proteolytic cleavage motifs. The synthetic heptadecapeptide potently inhibits adenylate cyclase in CHO(ORL1+) cells in culture and induces hyperalgesia when administered intracerebroventricularly to mice. Taken together, these data indicate that the newly discovered heptadecapeptide is an endogenous agonist of the ORL1 receptor and that it may be endowed with pro-nociceptive properties.