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Molecular Pharmacology

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Research ArticleArticle

Functional Selectivity in CB2 Cannabinoid Receptor Signaling and Regulation: Implications for the Therapeutic Potential of CB2 Ligands

Brady K. Atwood, James Wager-Miller, Christopher Haskins, Alex Straiker and Ken Mackie
Molecular Pharmacology February 2012, 81 (2) 250-263; DOI: https://doi.org/10.1124/mol.111.074013
Brady K. Atwood
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James Wager-Miller
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Christopher Haskins
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Alex Straiker
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Ken Mackie
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Abstract

Receptor internalization increases the flexibility and scope of G protein-coupled receptor (GPCR) signaling. CB1 and CB2 cannabinoid receptors undergo internalization after sustained exposure to agonists. However, it is not known whether different agonists internalize CB2 to different extents. Because CB2 is a promising therapeutic target, understanding its trafficking in response to different agonists is necessary for a complete understanding of its biology. Here we profile a number of cannabinoid receptor ligands and provide evidence for marked functional selectivity of cannabinoid receptor internalization. Classic, aminoalkylindole, bicyclic, cannabilactone, iminothiazole cannabinoid, and endocannabinoid ligands varied greatly in their effects on CB1 and CB2 trafficking. Our most striking finding was that (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone (WIN55,212-2) (and other aminoalkylindoles) failed to promote CB2 receptor internalization, whereas 5-(1,1-dimethylheptyl)-2-(5-hydroxy-2-(3-hydroxypropyl)cyclohexyl)phenol (CP55,940) robustly internalized CB2 receptors. Furthermore, WIN55,212-2 competitively antagonized CP55,940-induced CB2 internalization. Despite these differences in internalization, both compounds activated CB2 receptors as measured by extracellular signal-regulated kinase 1/2 phosphorylation and recruitment of β-arrestin2 to the membrane. In contrast, whereas CP55,940 inhibited voltage-gated calcium channels via CB2 receptor activation, WIN55,212-2 was ineffective on its own and antagonized the effects of CP55,940. On the basis of the differences we found between these two ligands, we also tested the effects of other cannabinoids on these signaling pathways and found additional evidence for functional selectivity of CB2 ligands. These novel data highlight that WIN55,212-2 and other cannabinoids show strong functional selectivity at CB2 receptors and suggest that different classes of CB2 ligands may produce diverse physiological effects, emphasizing that each class needs to be separately evaluated for therapeutic efficacy.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA011322, DA021696, DA009158]; and the National Institutes of Health National Institute for Research Resources [Grant RR025761].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.111.074013.

  • ABBREVIATIONS:

    2-AG
    2-arachidonoylglycerol
    A-836339
    N-[3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2-ylidene]-2,2,3,3-tetramethylcyclopropane-1-carboxamide
    AEA
    anandamide
    AM1241
    (2-iodo-5-nitrophenyl)-[1-[(1-methylpiperidin-2-yl)methyl]indol-3-yl]methanone
    AM1710
    3-(1,1-dimethyl-heptyl)-1-hydroxy-9-methoxy-benzo(c)chromen-6-one
    AM630
    iodopravadoline
    BSA
    bovine serum albumin
    CB1
    cannabinoid receptor subtype 1
    CB2
    cannabinoid receptor subtype 2
    CP47,497
    2-[(1R,3S)-3-hydroxycyclohexyl]- 5-(2-methyloctan-2-yl)phenol
    CP55,940
    5-(1,1-dimethylheptyl)-2-(5-hydroxy-2-(3-hydroxypropyl)cyclohexyl)phenol
    ECS
    extracellular solution
    ERK
    extracellular signal-regulated kinase
    FAAH
    fatty acid amide hydrolase
    GPCR
    G-protein-coupled receptor
    GW405833
    1-(2,3-dichlorobenzoyl)-5-methoxy-2-methyl-3-[2-(4-morpholinyl)ethyl]-1H-indole
    HA
    hemagglutinin 11
    HBS
    HEPES-buffered saline
    h
    human
    HEK
    human embryonic kidney
    HU-210
    Δ8-tetrahydrocannabinol dimethyl heptyl
    HU-308
    [(1R,2R,5R)-2-[2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl]-7,7-dimethyl-4-bicyclo[3.1.1]hept-3-enyl] methanol
    JWH015
    (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone
    JWH018
    naphthalen-1-yl-(1-pentylindol-3-yl)methanone
    JWH133
    (6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro -6,6,9-trimethyl-6H-dibenzo[b,d]pyran
    JZL184
    4-nitrophenyl-4-[bis(1,3-benzodioxol-5-yl)(hydroxy)methyl]piperidine-1-carboxylate
    m
    mouse
    MAPK
    mitogen-activated protein kinase
    MGL
    monoacylglycerol lipase
    mRFP
    modified red fluorescent protein
    PBS
    phosphate-buffered saline
    PFA
    paraformaldehyde
    pplss
    preprolactin signal sequence
    PTX
    pertussis toxin
    r
    rat
    SR141716
    rimonabant
    SR144528
    N-((1S)-endo-1,3,3-trimethyl bicyclo heptan-2-yl)-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide)
    SR144528
    N-[(1S)-endo-1,3,3-trimethylbicyclo [2.2.1]heptan2-yl]-5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-1H-pyrazole-3-carboxamide
    TBS
    Tris-buffered saline
    THC
    Δ9-tetrahydrocannabinol
    THCV
    tetrahydrocannabivarin
    URB597
    [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate
    VGCC
    voltage-gated calcium channel
    WIN55,212-2
    (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone.

  • Received June 8, 2011.
  • Accepted November 7, 2011.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (2)
Molecular Pharmacology
Vol. 81, Issue 2
1 Feb 2012
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Research ArticleArticle

Functionally Selective CB2 Ligands

Brady K. Atwood, James Wager-Miller, Christopher Haskins, Alex Straiker and Ken Mackie
Molecular Pharmacology February 1, 2012, 81 (2) 250-263; DOI: https://doi.org/10.1124/mol.111.074013

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Research ArticleArticle

Functionally Selective CB2 Ligands

Brady K. Atwood, James Wager-Miller, Christopher Haskins, Alex Straiker and Ken Mackie
Molecular Pharmacology February 1, 2012, 81 (2) 250-263; DOI: https://doi.org/10.1124/mol.111.074013
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