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Human kappa opiate receptor second extracellular loop elevates dynorphin's affinity for human mu/kappa chimeras

J B Wang1, P S Johnson, J M Wu

  • 1Molecular Neurobiology Branch, National Institute on Drug Abuse, Baltimore, Maryland.

The Journal of Biological Chemistry
|October 21, 1994
PubMed
Summary

The second extracellular loop of human opiate receptors significantly influences peptide ligand recognition. Replacing this domain in mu-opiate receptors enhances affinity for dynorphin peptides.

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Area of Science:

  • Pharmacology
  • Molecular Biology
  • Neuroscience

Background:

  • Human opiate receptors (mu, delta, kappa) mediate diverse physiological effects.
  • Ligand binding specificity is determined by receptor structure, particularly extracellular loops.
  • Understanding these interactions is crucial for developing targeted analgesics.

Purpose of the Study:

  • To investigate the role of the second extracellular loop (EL2) in human opiate receptor ligand selectivity.
  • To determine if EL2 sequences dictate the differential recognition of peptide and nonpeptide ligands.

Main Methods:

  • Construction of a chimeric human mu-opiate receptor with the EL2 domain from the human kappa-opiate receptor.
  • Radioligand binding assays to determine receptor affinity for various opioid peptides and small molecules.

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  • Functional assays measuring G-protein coupling via inhibition of adenyl cyclase activity.

    • Main Results:

    • The chimeric receptor exhibited a 250-fold increase in affinity for dynorphin peptides (e.g., dynorphin A-(1-17), alpha-neoendorphin) compared to the wild-type mu receptor.
    • The chimera retained high affinity for mu-selective ligands (morphine, [D-Ala2,MePhe4,Gly-ol5]enkephalin) and kappa-selective U50,488.
    • Effective G-protein coupling was observed, with dynorphin A-(1-17) effectively inhibiting adenyl cyclase activity.

    Conclusions:

    • The second extracellular loop of human opiate receptors plays a critical role in dynorphin peptide recognition.
    • EL2 sequences contribute significantly to the kappa receptor's selectivity for dynorphin peptides.
    • This finding has implications for understanding opioid receptor function and designing selective therapeutics.