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Vol. 55, Issue 2, 324-331, February 1999
-Opioid Receptors by Nociceptin and
Dynorphin A
Institut de Pharmacologie et de Biologie Structurale, Centre
National de la Recherche Scientifique, Toulouse, France
To understand how two structurally analogous ligand-receptor systems,
the nociceptin/opioid receptor-like 1 (ORL1) and dynorphin A/
-opioid
receptor 1 (KOR1) systems, achieve selectivity, receptor chimeras were
generated and analyzed. Replacing discrete domains located between the
N-terminus and top of the third transmembrane helix of the KOR1 by the
homologous domains of the ORL1 receptor yields hybrid receptors, which,
in comparison with the parent KOR1, display up to 300-fold increased
affinity but low sensitivity toward nociceptin, and unaltered (high)
affinity and sensitivity toward dynorphin A. These substitutions
contribute elements for binding of nociceptin but do not suppress
determinants necessary for binding and potency of dynorphin A. More
importantly, further replacement in these chimeras of the second
extracellular loop with that of the ORL1 receptor fully restores
responsiveness to nociceptin without impairing responsiveness to
dynorphin A. A bifunctional hybrid receptor has thus been identified
that binds and responds to both nociceptin and dynorphin A as
efficiently as the ORL1 receptor does to nociceptin and the KOR1 to
dynorphin A. Together, these results suggest that distinct peptide
activation mechanisms operate in the two receptor systems. In
particular, the second extracellular receptor loop appears to be an
absolute requirement for activation of the ORL1 receptor by nociceptin, but not for activation of the KOR1 by dynorphin A.
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