Phytocannabinoid-dependent mTORC1 regulation is dependent upon inositol polyphosphate multikinase activity.
Phytocannabinoid-dependent mTORC1 regulation is dependent upon inositol polyphosphate multikinase activity.
复制标题
植物大麻素依赖性mTORC 1调节依赖于肌醇多磷酸多激酶活性。
DOI：
10.1111/bph.15351
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发表时间：
2021-03
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
大麻二酚（CBD）已被证明在临床前疾病模型中差异调节雷帕霉素复合物1（mTORC 1）的机制靶点，其中它降低癫痫和癌症模型中的活性，并增加多发性硬化症（MS）和精神病模型中的活性。在这里，我们研究了植物大麻素对mTORC 1的影响，并确定了分子机制。一种新的机制，植物大麻素被确定使用易处理的模型系统，Dictyosteelium discoideum。使用小鼠胚胎成纤维细胞，我们进一步验证了这种新的作用机制。我们使用来自健康个体和MS患者（MS）的细胞证明了临床相关性。CBD和更丰富的大麻萜酚（CBG）都能增强D.盘状突。我们确定了这种效应的机制，涉及肌醇多磷酸多激酶（IPMK），其中IPMK表达升高逆转了对植物大麻素的反应，降低了治疗后的mTORC 1活性，为植物大麻素的作用提供了新的见解。我们使用小鼠胚胎成纤维细胞进一步验证了这一机制。在原代人外周血单核细胞中显示了这种作用的临床相关性，其中CBD和CBG处理增加了来自健康个体的细胞中的mTORC 1活性，并降低了来自BRMS的细胞中的mTORC 1活性。我们的研究结果表明，CBD和丰富的CBG通过依赖于上游IPMK信号通路活性的机制差异调节mTORC 1信号传导，与mTOR相关疾病（包括MS）的治疗具有潜在相关性。
Cannabidiol (CBD) has been shown to differentially regulate the mechanistic target of rapamycin complex 1 (mTORC1) in preclinical models of disease, where it reduces activity in models of epilepsies and cancer and increases it in models of multiple sclerosis (MS) and psychosis. Here, we investigate the effects of phytocannabinoids on mTORC1 and define a molecular mechanism. A novel mechanism for phytocannabinoids was identified using the tractable model system, Dictyostelium discoideum. Using mouse embryonic fibroblasts, we further validate this new mechanism of action. We demonstrate clinical relevance using cells derived from healthy individuals and from people with MS (pwMS). Both CBD and the more abundant cannabigerol (CBG) enhance mTORC1 activity in D. discoideum. We identify a mechanism for this effect involving inositol polyphosphate multikinase (IPMK), where elevated IPMK expression reverses the response to phytocannabinoids, decreasing mTORC1 activity upon treatment, providing new insight on phytocannabinoids' actions. We further validated this mechanism using mouse embryonic fibroblasts. Clinical relevance of this effect was shown in primary human peripheral blood mononuclear cells, where CBD and CBG treatment increased mTORC1 activity in cells derived from healthy individuals and decreased mTORC1 activity in cells derived from pwMS. Our findings suggest that both CBD and the abundant CBG differentially regulate mTORC1 signalling through a mechanism dependent on the activity of the upstream IPMK signalling pathway, with potential relevance to the treatment of mTOR‐related disorders, including MS.
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DOI：
10.1016/j.jchromb.2009.11.004
发表时间：
2009-12-15
影响因子：
3
作者：
De Backer, Benjamin;Debrus, Benjamin;Charlier, Corinne
通讯作者：
Charlier, Corinne
DOI：
10.1124/jpet.114.218768
发表时间：
2015-01-01
影响因子：
3.5
作者：
Chang, Pishan;Zuckermann, Alexandra M. E.;Williams, Robin S. B.
通讯作者：
Williams, Robin S. B.
影响因子：
14.5
作者：
Bar-Or, A;Nuttall, RK;Yong, VW
通讯作者：
Yong, VW
影响因子：
3.4
作者：
Gobira, Pedro H.;Vilela, Luciano R.;Moreira, Fabricio A.
通讯作者：
Moreira, Fabricio A.
影响因子：
4.3
作者：
Kelly E;Sharma D;Wilkinson CJ;Williams RSB
通讯作者：
Williams RSB