Moving from the orphanin FQ receptor to an opioid receptor using four point mutations.
It is unclear how receptor/ligand families that are evolutionarily closely related achieve functional separation. To address this question, we focus here on the newly discovered Orphanin FQ, a peptide homologous to the opioid peptide Dynorphin, and its receptor, the Orphanin FQ receptor, which is highly homologous to the opioid receptors. In spite of this high degree of homology in terms of both ligands and receptors, there is little direct cross-talk between the Orphanin FQ system and the endogenous opioid system. Thus, the opioid peptides show either relatively low affinity or no affinity toward the Orphanin FQ receptor; conversely, Orphanin FQ has no affinity toward any of the opioid receptors. We sought to investigate the molecular basis of such discrimination by attempting to reverse it and endowing the Orphanin FQ receptor with the ability to bind opioids. We report that by mutating as few as four amino acids, we can produce a receptor that recognizes pro-Dynorphin products with very high affinity and yet still binds Orphanin FQ as well as the wild-type receptor. This suggests that the Orphanin FQ receptor has developed features that specifically exclude the opioids and that these features are distinct from those required for the high affinity binding of its own endogenous ligand.
Meng
F
F
Mental Health Research Institute, University of Michigan, Ann Arbor, Michigan 48109, USA. mengf@umich.edu
Taylor
L P
LP
Hoversten
M T
MT
Ueda
Y
Y
Ardati
A
A
Reinscheid
R K
RK
Monsma
F J
FJ
Watson
S J
SJ
Civelli
O
O
Akil
H
H
D000700:Analgesics / Q000378:metabolism; D000818:Animals; D001575:Benzomorphans / Q000378:metabolism; D004399:Dynorphins / Q000378:metabolism; D008958:Models, Molecular; D009271:Naltrexone / Q000031:analogs & derivatives / Q000378:metabolism; D009292:Narcotic Antagonists / Q000378:metabolism; D017354:Point Mutation; D051381:Rats; D011957:Receptors, Opioid / Q000235:genetics* / Q000378:metabolism; D000094942:Nociceptin Receptor
D000700:Analgesics; D001575:Benzomorphans; D004399:Dynorphins; D009271:Naltrexone; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; C055382:naltrindole; C027248:bremazocine; C000722285:Oprl1 protein, rat