Phytocannabinoid-dependent mTORC1 regulation is dependent upon inositol polyphosphate multikinase activity.
Joseph L Damstra-Oddy1, Eleanor C Warren1, Christopher J Perry1
1Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, UK.
British Journal of Pharmacology
|December 21, 2020
Summary
Cannabidiol (CBD) and cannabigerol (CBG) influence mTORC1 activity through a novel mechanism involving inositol polyphosphate multikinase (IPMK). This pathway
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Cannabidiol (CBD) exhibits varied effects on mTORC1 signaling across different diseases.
- Preclinical models show CBD reduces mTORC1 in epilepsy and cancer, but increases it in multiple sclerosis (MS) and psychosis.
Purpose of the Study:
- To investigate the impact of phytocannabinoids on mTORC1 signaling.
- To elucidate the molecular mechanism underlying phytocannabinoid action on mTORC1.
- To assess the clinical relevance of these findings in human cells.
Main Methods:
- Utilized Dictyostelium discoideum as a model system to identify a novel phytocannabinoid mechanism.
- Validated the mechanism in mouse embryonic fibroblasts.
- Examined the effects in peripheral blood mononuclear cells from healthy individuals and people with MS (pwMS).
Main Results:
- Both CBD and cannabigerol (CBG) were found to enhance mTORC1 activity in D. discoideum.
- A mechanism involving inositol polyphosphate multikinase (IPMK) was identified; elevated IPMK reversed phytocannabinoid-induced mTORC1 changes.
- In human cells, CBD and CBG increased mTORC1 activity in healthy individuals but decreased it in pwMS.
Conclusions:
- CBD and CBG differentially regulate mTORC1 signaling via an IPMK-dependent pathway.
- This mechanism has potential implications for treating mTOR-related disorders, including MS.
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