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Publication - Professor Jeremy Henley

    The F238L Point Mutation in the Cannabinoid Type 1 Receptor Enhances Basal Endocytosis via Lipid Rafts


    Wickert, M, Hildick, K, Baillie, GL, Jelinek, R, Rey, AA, Monory, K, Schneider, M, Ross, RA, Henley, JM & Lutz, B, 2018, ‘The F238L Point Mutation in the Cannabinoid Type 1 Receptor Enhances Basal Endocytosis via Lipid Rafts’. Frontiers in Molecular Neuroscience, vol 11.


    Defining functional domains and amino acid residues in G protein coupled
    receptors (GPCRs) represent an important way to improve rational drug
    design for this major class of drug targets. The cannabinoid type 1
    (CB1) receptor is one of the most abundant GPCRs in the central nervous
    system and is involved in many physiological and pathophysiological
    processes. Interestingly, cannabinoid type 1 receptor with a
    phenylalanine 238 to leucine mutation (CB1F238L) has been already linked
    to a number of both in vitro and in vivo alterations.
    While CB1F238L causes significantly reduced presynaptic neurotransmitter
    release at the cellular level, behaviorally this mutation induces
    increased risk taking, social play behavior and reward sensitivity in
    rats. However, the molecular mechanisms underlying these changes are not
    fully understood. In this study, we tested whether the F238L mutation
    affects trafficking and axonal/presynaptic polarization of the CB1
    receptor in vitro. Steady state or ligand modulated surface
    expression and lipid raft association was analyzed in human embryonic
    kidney 293 (HEK293) cells stably expressing either wild-type cannabinoid
    type 1 receptor (CB1wt) or CB1F238L receptor. Axonal/presynaptic
    polarization of the CB1F238L receptor was assessed in transfected
    primary hippocampal neurons. We show that in vitro the CB1F238L
    receptor displays increased association with lipid rafts, which
    coincides with increased lipid raft mediated constitutive endocytosis,
    leading to a reduction in steady state surface expression of the
    CB1F238L receptor. Furthermore, the CB1F238L receptor showed increased
    axonal polarization in primary hippocampal neurons. These data
    demonstrate that endocytosis of the CB1 receptor is an important
    mediator of axonal/presynaptic polarization and that phenylalanine 238
    plays a key role in CB1 receptor trafficking and axonal polarization.

    Full details in the University publications repository