Jpn. J. Pharmacol. 83 (4), 306-311 (2000)


Endomorphin-1 Discriminates the m-Opioid Receptor From the d- and k-
Opioid Receptors by Recognizing the Difference
in Multiple Regions

Soichiro Ide, Kyoko Sakano, Takahiro Seki, Shinichiro Awamura, Masabumi Minami and Masamichi Satoh*


Department of Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan
*╩To whom correspondence should be addressed.

Abstract: Endomorphin-1 is a novel endogenous peptide that is highly selective for the m-opioid receptor over the d- and k-opioid receptors. The structural basis of high selectivity of endomorphin-1 to the m-opioid receptor was examined using chimeric receptors between m- and d-opioid receptors and those between m- and k-opioid receptors. The chimeric receptors were constructed by using restriction enzyme sites intrinsically possessed by or introduced to the m-, d- and k-opioid receptor cDNAs. The junctions for the construction were located at the first intracellular loop (Bbs╩I site), third transmembrane domain (Afl╩III site) and fifth transmembrane domain (Bgl╩II site). The competitive binding assay using chimeric receptors revealed that the region from the Bbs╩I site to the Afl╩III site, including the first extracellular loop, contributes to the discrimination between m- and d-opioid receptors by endomorphin-1 more than any other regions. However, the region from the Afl╩III site to the Bgl╩II site and that from the Bgl╩II site to the carboxy terminal also somewhat contribute to the discrimination between m- and d-opioid receptors. For the discrimination between m- and k-opioid receptors, two regions, that is, the region from the Bbs╩I site to the Afl╩III site and that from the Bgl╩II site to the carboxy terminal, were shown to be important. The present results show that endomorphin-1 discriminates the m-opioid receptor from the other two types of opioid receptors by recognizing the differences in several amino acid residues widely distributed through the receptor structure. We previously reported that DAMGO, a synthetic highly m-selective peptide, discriminates between m- and d-opioid receptors by recognizing the difference in only one amino acid residue and discriminates between m- and k-opioid receptors by recognizing the difference in four residues localized in the restricted region. Although both endomorphin-1 and DAMGO are m-opioid receptor selective peptides, molecular mechanisms for m-selectivity are different between these peptides.

Keywords: Endomorphin-1, Opioid receptor, Chimeric receptor, Binding selectivity,
Competitive binding assay


Copyrightę The Japanese Pharmacological Society 2000

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