Modulation of L-α-Lysophosphatidylinositol/GPR55 Mitogen-activated Protein Kinase (MAPK) Signaling by Cannabinoids
Modulation of L-α-Lysophosphatidylinositol/GPR55 Mitogen-activated Protein Kinase (MAPK) Signaling by Cannabinoids
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DOI：
10.1074/jbc.m111.296020
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发表时间：
2012-01-02
影响因子：
4.8
通讯作者：
Ross, Ruth A.
中科院分区：
文献类型：
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作者：
Anavi-Goffer, Sharon;Baillie, Gemma;Ross, Ruth A.
GPR 55可被L-α-溶血磷脂酰肌醇（LPI）激活，但也可被某些大麻素激活。在这项研究中，我们研究了各种大麻素的GPR 55药理学，包括CB 1受体拮抗剂利莫那班（R），CB 2受体激动剂和大麻成分的类似物。为了测试ERK 1/2磷酸化，使用AlphaScreen（R）SureFire（R）测定法建立了一种主要的下游信号传导途径，该途径传递了高通量系统GPR 55的LPI诱导的活化。在这里，我们表明，CB 1受体拮抗剂可以单独作为激动剂和抑制剂的LPI信号在相同的测定条件下。本研究澄清了围绕SR 141716 A的GPR 55介导作用的争议;一些报告指出该化合物是一种激动剂，一些报告指出具有拮抗作用。相反，我们报道CB 2配体GW 405833单独作为GPR 55的部分激动剂并增强LPI信号传导。GPR 55与疼痛传递有关，因此我们的研究结果表明，该受体可能负责某些CB 2受体配体的一些抗伤害性作用。植物大麻素Delta（9）-tetrahydrocannabivarin、cannabidivarin和cannabigerovarin也是LPI的有效抑制剂。这些大麻成分可能代表靶向GPR 55的新疗法。
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.