MOLECULAR STUDIES OF A NEW OPIOID RECEPTOR

  • Grandy, David, (PI)

    Project: Research project

    Description

    Three major classes of opioid receptors, mu(mu), delta (delta) and kappa
    (kappa), have been defined based on differences in their pharmacology,
    physiology and tissue distribution. When stimulated in vivo the opioid
    receptors activate a cascade of intracellular reactions involving
    adenylyl cyclase, calcium channels and potassium channels, which result
    in many of the classical effects of opiate intoxication including
    euphoria, analgesia and physical dependence. The molecular
    characterization of the opioid receptors has been slow due to several
    factors, perhaps the most important of which being that they are
    intrinsic membrane proteins which are difficult to solubilize in active
    form and they are expressed in relatively low amounts. Recently these
    difficulties were overcome by the expression cloning of a mouse delta
    opioid receptor subtype from the neuroblastoma X glioma cell line NG108-
    15. The primary known as the G protein-coupled receptors. In light of
    these recent reports we re-examined the sequence of an orphan receptor
    clone which we had obtained by degenerate PCR. This cDNA clone, referred
    to as R21, encodes a novel G protein-coupled receptor which shares
    significant sequence identity with the recently published mouse delta
    opioid receptor. Based on the conservation of key amino acid residues
    and the overall homology between R21 and the mouse delta opioid receptor
    we predict that R21 is a member of the opioid receptor family. To test
    this hypothesis we propose to pharmacologically characterize the receptor
    encoded by R21 and investigate the affect its stimulation has on adenylyl
    cyclase and a voltage-dependent outwardly rectifying potassium
    conductance. Once pharmacologically defined the tissue regulated the rat
    R21 gene will be characterized. The human homologue of the R21 gene will
    also be characterized to identify markers that can be used i genetic
    linkage and association studies of HR21 and human disease. Eventually
    the mouse gene, MR21, will be target and knocked out. These transgenic
    mice will be a valuable model system in which to evaluate the receptor's
    role in processes ranging from synaptic transmission to behavior.
    StatusFinished
    Effective start/end date12/10/933/31/02

    Funding

    • National Institutes of Health: $179,942.00
    • National Institutes of Health
    • National Institutes of Health: $143,889.00
    • National Institutes of Health
    • National Institutes of Health
    • National Institutes of Health
    • National Institutes of Health

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    kappa Opioid Receptor
    Opioid Receptors
    Opiate Alkaloids
    delta Opioid Receptor
    mu Opioid Receptor
    Potassium Channels
    Calcium Channels
    Genes
    G-Protein-Coupled Receptors
    Organism Cloning
    Opioid Analgesics
    Tissue Distribution
    Pharmacology
    Synaptic Transmission
    Analgesia
    Complementary DNA
    Adenylyl Cyclases
    Genetic Linkage
    Amino Acids
    Clone Cells

    ASJC

    • Medicine(all)