Scientists at Stony Brook University discovered the mechanism by which the main components of marijuana, THC and CBD, are transported within the cell.
The team of researchers, led by Dale Deutsch, Martin Kaczocha and Matthew Elmes characterized the binding of THC and CBD to fatty-acid binding proteins (FABPs) that act like shuttles in the cell.
CBD and THC are identical in structure save for one bond, but have vastly different effects on
the body.
THC can be seen as the “evil twin,” as it activates cannabinoid receptors and causes the psychoactive effects of marijuana.
CBD, on the other hand, is the “good twin” and does not cause any psychoactive effects.
Understanding the way CBD works in the cell is important because CBD has shown promise in treating cases of childhood epilepsy and has neuroprotective and antidepressant qualities.
Both THC and CBD are found in the cell membrane due to their hydrophobic nature.
“We know that these molecules do in fact localize in the cell membrane, but we did not know how they are transported through the cell in the aqueous cytoplasm,” Elmes, a Ph.D. student in Deutsch’s lab, said.
It was previously thought that CBD worked by inhibiting fatty acid amide hydrolase (FAAH), the “garbage can” that would discard of anandamide. The premise was that if the garbage can could no longer work, then there would be an excess of anandamide and its positive effects.
Anandamide is the neurotransmitter naturally present within the body. Components of marijuana mimic some of the effects of anandamide.
Deutsch and his team were the first to show that while CBD inhibits FAAH in the cells of mice and rats it did not inhibit FAAH in human cells.
Therefore, in humans, the rise in anandamide as a result of marijuana usage could not be due to the garbage can being disabled.
Instead, Deutsch and his team found that there is a shuttle protein, FABP, that acts as a chaperone to bring THC and CBD from the cell membrane to the FAAH garbage can.
Normally, FABPs transport anandamide to FAAH. However, when marijuana is used, THC and CBD are present and compete with the anandamide to bind to the shuttle.
Since there is competition, less anandamide will be able to bind and be ultimately degraded by FAAH. As a result, there will be more anandamide present and more of its positive effects.
The team initially used computer simulations to predict the binding of THC and CBD to FABPs and found there to be a favorable free energy of binding.
“Interestingly, the affinities of FABP for THC and CBD are almost exactly the same as the affinity for anandamide, so it makes sense that they could be competing for binding,” Elmes said.
Scientists quantified this relationship and the binding of THC and CBD to the FABPs through a fluorescence-binding assay.
First, the baseline fluorescence level was measured by flooding FABPs with a fluorescent probe.
Then CBD and THC were added. They observed a decrease in the fluorescence level, suggesting that the CBD and THC were able to bind to the FABPs, displacing the fluorescent probe that was initially binding.
“It’s one step in the right direction to understand how CBD might be working to treat things like childhood epilepsy,” Elmes said.
The team has started developing inhibitors of FABPs to increase anandamide levels in the body. One inhibitor they developed, SBFI26,raised anandamide levels in mice and and had pain-reducing effects. The team also plans to further investigate how THC and CBD work in other body systems and what players are involved to best harness the positive effects of marijuana.
