ORL1, A NOVEL MEMBER OF THE OPIOID RECEPTOR FAMILY - CLONING, FUNCTIONAL EXPRESSION AND LOCALIZATION

Selective PCR amplification of human and mouse genomic DNAs with oligo nucleotides encoding highly conserved regions of the delta-opioid and somatostatin receptors generated a human DNA probe (hOP01, 761 bp) and its murine counterpart (mOP86, 447 bp). hOP01 was used to screen a cD NA library from human brainstem. A clone (named hORL1) was isolated, s equenced and found to encode a protein of 370 amino acids whose primar y structure displays the seven putative membrane-spanning domains of a G protein-coupled membrane receptor. The hORL1 receptor is most close ly related to opioid receptors not only on structural (sequence) but a lso on functional grounds: hORL1 is 49-50% identical to the murine mu- , delta- and kappa-opioid receptors and, in CHO-K1 cells stably transf ected with a pRc/CMV:hORL1 construct, ORL1 mediates inhibition of aden ylyl cyclase by etorphine, a 'universal' (nonselective) opiate agonist . Yet, hORL1 appears not to be a typical opioid receptor. Neither is i t a somatostatin or delta (N-allylnormetazocine) receptor. mRNAs hybri dizing with synthetic oligonucleotides complementary to mOP86 are pres ent in many regions of the mouse brain and spinal cord, particularly i n limbic (amygdala, hippocampus, septum, habenula,...) and hypothalami c structures. We conclude that the hORL1 receptor is a new member of t he opioid receptor family with a potential role in modulating a number of brain functions, including instinctive behaviours and emotions.