dictyNews

Electronic Edition

Volume 47, number 1

January 15, 2021



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Abstracts

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Phytocannabinoid-dependent mTORC1 regulation is dependent upon 

IPMK activity



Joseph L. Damstra-Oddy (1), Eleanor C. Warren (1), Christopher J. 

Perry (1), Yann Desfougères (2), John-Mark K. Fitzpatrick (3), 

Judith Schaf (1), Lisa Costelloe (4), William Hind (5), Eric J. 

Downer (3), Adolfo Saiardi (2) and Robin S.B. Williams (1)* 



(1) Centre for Biomedical Sciences, School of Biological Sciences, 

Royal Holloway University of London, Egham, UK. 

(2) Laboratory for Molecular Cell Biology, University College 

London, London, UK. 

(3) School of Medicine, Trinity College Dublin, Dublin, Ireland. 

(4) Department of Neurology, Beaumont Hospital, Dublin, Ireland. 

(5) GW Research Ltd, Histon, United Kingdom.



British Journal of Pharmacology, see DOI: 10.1111/bph.15351 



Background and Purpose: 

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.



Experimental Approach: 

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).



Key Results: 

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 inverses 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.



Conclusion and Implications: 

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.



submitted by: Robin Williams [[log in to unmask]]

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