Antagonist efficacy in MORS196L mutant is affected by the interaction between transmembrane domains of the opioid receptor

Patricia A. Claude-Geppert, Jiahui Liu, Jonathan Solberg, Laurie J. Erickson-Herbrandson, Horace H Loh, Ping-Yee Law

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

In a previous study, we demonstrated that antagonists such as naloxone or naltrexone acted as full agonists at the μ-opioid receptor (MOR)/δ-opioid receptor (DOR) chimeric receptor (μδ2, where the DOR sequence from the first extracellular loop to the carboxyl terminus was spliced to the MOR sequence) when a conserved serine residue in transmembrane 4 (TM4) was mutated to leucine. However, when Ser196 in the TM4 of MOR was mutated to Leu, antagonists exhibited partial agonistic properties. Since molecular modeling studies suggested transmembrane movement during receptor activation, the observed partial agonistic properties could be due to TM1 and TM7 interaction. Hence, MOR/DOR chimeric mutant receptors with the MOR TM1 and TM7 sequence (μδ2μ7S196L) or with the MOR TM1 and TM6/7 sequence (μδ2μ67S196L) were constructed to test such a hypothesis. Using four tests of opioid receptor activation, we found that the opioid antagonists were full agonists in chimeric mutant receptor if the TM1 and TM7 were from different opioid receptors. Additionally, when two of the TM7 amino acid residues of MORS196L receptor mutants were mutated (T327A and C330S), resulting in a mutant receptor with DOR TM7 sequence, opioid antagonist naloxone exhibited full agonistic properties. These data suggest that the efficacy of opioid antagonists in the Ser 196 mutant can be affected by the interaction between TM1 and TM7.

Original languageEnglish (US)
Pages (from-to)216-226
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume313
Issue number1
DOIs
StatePublished - Apr 2005

Fingerprint

Dive into the research topics of 'Antagonist efficacy in MORS196L mutant is affected by the interaction between transmembrane domains of the opioid receptor'. Together they form a unique fingerprint.

Cite this