The third extracellular loop of the μ opioid receptor is important for agonist selectivity

J. C. Xue, C. Chen, J. Zhu, S. P. Kunapuli, J. K. De Riel, L. Yu, L. Y. Liu-Chen

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Abstract

To investigate the interaction between the μ opioid receptor and its ligands, we compared the binding of μ-selective ligands to two μ/κ chimeric opioid receptors and to μ and κ receptors. The two chimeras were constructed from cloned rat μ and κ receptors in which a segment from the middle of the third intracellular loop to the C terminus was exchanged. When this portion of the κ receptor was replaced by that of the μ receptor, affinities of μ selective agonists, DAMGO (Tyr-D-Ala-Gly-NMePhe-Gly-ol), PL017 (Tyr-Pro-NMePhe-D-Pro-NH2), sufentanil, and morphine, were greatly increased as compared to those for the κ receptor. Conversely, when this region of the preceptor was substituted by that of the κ receptor, affinities for these agonists were substantially decreased as compared with those of the μ receptor. Unlike selective agonists, the μ-selective antagonist, CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-penicillamine-Thr-NH2), displayed a low affinity for both chimeric receptors, similar to that of the κ receptor. Thus, the region from the middle of the third intracellular loop to the C terminus of the μ receptor is important for the binding of selective agonists. Conversely, the determinants for selective binding of the antagonist CTAP reside in a more extended region of the receptor.

Original languageEnglish (US)
Pages (from-to)12977-12979
Number of pages3
JournalJournal of Biological Chemistry
Volume270
Issue number22
StatePublished - 1995
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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