Modulation of L-alpha-Lysophosphatidylinositol/GPR55 Mitogen-activated Protein Kinase (MAPK) Signaling by Cannabinoids. / Anavi-Goffer, Sharon; Baillie, Gemma; Irving, Andrew J.; Gertsch, Juerg; Greig, Iain R.; Pertwee, Roger G.; Ross, Ruth A.
In: Journal of Biological Chemistry, Vol. 287, No. 1, 02.01.2012, p. 91-104.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Modulation of L-alpha-Lysophosphatidylinositol/GPR55 Mitogen-activated Protein Kinase (MAPK) Signaling by Cannabinoids
A1 - Anavi-Goffer,Sharon
A1 - Baillie,Gemma
A1 - Irving,Andrew J.
A1 - Gertsch,Juerg
A1 - Greig,Iain R.
A1 - Pertwee,Roger G.
A1 - Ross,Ruth A.
AU - Anavi-Goffer,Sharon
AU - Baillie,Gemma
AU - Irving,Andrew J.
AU - Gertsch,Juerg
AU - Greig,Iain R.
AU - Pertwee,Roger G.
AU - Ross,Ruth A.
PY - 2012/1/2
Y1 - 2012/1/2
N2 - <p>GPR55 is activated by L-alpha-lysophosphatidylinositol (LPI) but also by certain cannabinoids. In this study, we investigated the GPR55 pharmacology of various cannabinoids, including analogues of the CB1 receptor antagonist Rimonabant (R), CB2 receptor agonists, and Cannabis sativa constituents. To test ERK1/2 phosphorylation, a primary downstream signaling pathway that conveys LPI-induced activation of GPR55, a high throughput system, was established using the AlphaScreen (R) SureFire (R) assay. Here, we show that CB1 receptor antagonists can act both as agonists alone and as inhibitors of LPI signaling under the same assay conditions. This study clarifies the controversy surrounding the GPR55-mediated actions of SR141716A; some reports indicate the compound to be an agonist and some report antagonism. In contrast, we report that the CB2 ligand GW405833 behaves as a partial agonist of GPR55 alone and enhances LPI signaling. GPR55 has been implicated in pain transmission, and thus our results suggest that this receptor may be responsible for some of the antinociceptive actions of certain CB2 receptor ligands. The phytocannabinoids Delta(9)-tetrahydrocannabivarin, cannabidivarin, and cannabigerovarin are also potent inhibitors of LPI. These Cannabis sativa constituents may represent novel therapeutics targeting GPR55.</p>
AB - <p>GPR55 is activated by L-alpha-lysophosphatidylinositol (LPI) but also by certain cannabinoids. In this study, we investigated the GPR55 pharmacology of various cannabinoids, including analogues of the CB1 receptor antagonist Rimonabant (R), CB2 receptor agonists, and Cannabis sativa constituents. To test ERK1/2 phosphorylation, a primary downstream signaling pathway that conveys LPI-induced activation of GPR55, a high throughput system, was established using the AlphaScreen (R) SureFire (R) assay. Here, we show that CB1 receptor antagonists can act both as agonists alone and as inhibitors of LPI signaling under the same assay conditions. This study clarifies the controversy surrounding the GPR55-mediated actions of SR141716A; some reports indicate the compound to be an agonist and some report antagonism. In contrast, we report that the CB2 ligand GW405833 behaves as a partial agonist of GPR55 alone and enhances LPI signaling. GPR55 has been implicated in pain transmission, and thus our results suggest that this receptor may be responsible for some of the antinociceptive actions of certain CB2 receptor ligands. The phytocannabinoids Delta(9)-tetrahydrocannabivarin, cannabidivarin, and cannabigerovarin are also potent inhibitors of LPI. These Cannabis sativa constituents may represent novel therapeutics targeting GPR55.</p>
KW - L-ALPHA-LYSOPHOSPHATIDYLINOSITOL
KW - CANCER-CELL PROLIFERATION
KW - CB1 RECEPTOR ANTAGONIST
KW - B-RAF INHIBITORS
KW - ALLOSTERIC MODULATION
KW - PLANT CANNABINOIDS
KW - ENDOTHELIAL-CELLS
KW - NEUROPATHIC PAIN
KW - GPR55
KW - IDENTIFICATION
U2 - 10.1074/jbc.M111.296020
DO - 10.1074/jbc.M111.296020
M1 - Article
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 1
VL - 287
SP - 91
EP - 104
ER -